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Human   brain.  Mononuclear  cell   infiltration    and   congestion   of  vessels  in 
meninges  of  cerebrum  in  acute  epidemic  encephalitis. 


ACUTE 
EPIDEMIC  ENCEPHALITIS 

[LETHARGIC    ENCEPHALITIS] 

An  Investigation  by  The  Association  for 
Research  in  J\[ervous  and  TsAental  Diseases 


Report  of  the  Papers  and  Discussions  at  the 

Meeting  of  The  Association;  New  York  City, 

December  28th  and  29TH,  1920 


PREPARED  UNDER  THE  DIRECTION  OF 


WALTER  TIMME,  M.D.  GEORGE  H.  KIRBY,  M.  D. 

PEARCE  BAILEY,  M.D.  HUGH  T.  PATRICK,  M.D. 

LEWELLYS  F.  BARKER,  M.D.  BERNARD  SACHS,  M.D. 

SANGER  BROWN,  2D,  M.D.  WILLIAM  G.  SPILLER,  M.D. 

CHARLES  L.  DANA,  M.D.  ISRAEL  STRAUSS,  M.D. 

J.  RAMSEY  HUNT,  M.D.  E.  W.  TAYLOR,  M.D. 

FOSTER  KENNEDY,  M.D.  FREDERICK  TILNEY,  M.D. 
T.   H.  WEISENBURG,  M.D. 


4fr 


NEW   YORK 

PAUL  B.  HOEBER 

MCMXXI 


//*:<*- 


Copyright,  1921 

By  Paul  B.  Hoeber 


Published,  December,  192 1 


K 

■t  ? 


Printed  in  the  United  States  of  America 


OFFICERS  OF  THE  ASSOCIATION  FOR  RE- 
SEARCH IN  NERVOUS  AND  MENTAL 
DISEASES  192 1 

Walter  Timme,  M.D.,  New  York President 

E.  W.  Taylor,  M.D.,  Boston Vice-President 

Sanger  Brown,  2d,  M.D.,  New  York.  .    .    .    Secretary-Treasurer 


COMMISSION 


Walter  Timme,  M.D., 

New  York 
Pearce  Bailey,  M.D., 

New  York 
Lewellys  F.  Barker,  M.D., 

Baltimore 
Charles  L.  Dana,  M.D., 

New  York 
J.  Ramsay  Hunt,  M.D., 

New  York 
Foster  Kennedy,  M.D., 

New  York 
George  H.  Kirby,  M.D., 

New  York 


Hugh  T.  Patrick,  M.D., 

Chicago 
Bernard  Sachs,  M.D., 

New  York 
William  G.  Spiller,  M.D., 

Philadelphia 
Israel  Strauss,  M.D., 

New  York 
E.  W.  Taylor,  M.D., 

Boston 
Frederick  Tilney,  M.D., 

New  York 
T.  H.  Weisenburg,  M.D., 

Philadelphia 


VII 


ASSOCIATION  FOR  RESEARCH  IN  NERVOUS 
AND  MENTAL  DISEASES 

LIST  OF  CONTRIBUTORS 

Abrahamson,  Isador,  M.D. 

Clinical  Professor  of  Neurology,  New  York  University  and 

Bellevue  Medical  School; 

Associate  Neurologist,  Mt.  Sinai  Hospital,  New  York. 
Ayer,  James  B.,  M.D. 

Instructor  in  Neurology  and  Assistant  in  Neuropathology, 

Harvard  Medical  School,  Boston. 
Amoss,  Harold  L.,  M.D.,  P.H. 

Associate  Member,  The  Rockefeller  Institute,  New  York. 
Banzhaf,  E.  J.,  Ph.D. 

Director    Antitoxin    Laboratories,    Department    of   Health, 

New  York. 
Barker,  Lewellys  F.,  M.D. 

Professor   of  Clinical   Medicine,  Johns  Hopkins  University, 

Baltimore. 
Boyd,  William,  M.D. 

Professor  of  Pathology  and  Histology,  University  of  Manitoba, 

Winnipeg. 
Cadwalader,  William  B.,  M.D. 

Associate    in    Neurology    and    Neuropathology,    School    of 

Medicine,  University  of  Pennsylvania,  Philadelphia. 
Davis,  Thomas  K.,  M.D. 

Clinical  Instructor  in  Medicine,  Department  of  Neurology, 

Cornell  University  Medical  College,  New  York. 
Friesner,  Isidore,  M.D. 

Otologist,  Mt.  Sinai  Hospital,  New  York; 

Assistant  Aural  Surgeon,  Manhattan  Eye  and  Ear  Hospital, 

New  York. 
Griffith,  J.  P.  Crozer,  M.D. 

Professor  of  Pediatrics,   University  of  Pennsylvania,   Phila- 
delphia. 

ix 


x  ACUTE  EPIDEMIC  ENCEPHALITIS 

Grossman,  Morris,  M.D. 

Adjunct  Attending  Neurologist,  Mt.  Sinai  Hospital,  New  York. 
Hassin,  George  B.,  M.D. 

Associate    Professor    of    Neurology,    University    of    Illinois 

College  of  Medicine,  Chicago. 
Hohman,  Leslie  B.,  M.D. 

Assistant   Physician,    Phipps   Psychiatric   Clinic,   Baltimore. 
Holden,  Ward  A.,  M.D. 

Professor  of  Clinical  Ophthalmology,  Columbia  University, 

New  York. 
Howe,  Hubert  S.,  M.D. 

Associate  in  Neurology,   Columbia  University,   New  York; 

Assistant  Professor,   Department  of  Neurology,   New  York 

Post-Graduate  School  and  Hospital. 
Hunt,  J.  Ramsay,  M.D. 

Consulting  Neurologist,  Neurological  Institute,  New  York. 
Kennedy,  Foster,  M.D. 

Associate  Professor  of  Neurology,  Cornell  University  Medical 

College,  New  York; 

Visiting  Physician  in  Charge  of  the  Neurological  Department, 

Bellevue  Hospital,  New  York. 
Kirby,  George  H.;  M.D. 

Director,  New  York  State  Psychiatric  Institute; 

Professor  of  Psychiatry,  Cornell  University  Medical  College, 

New  York. 
Kraus,  Walter  M.,  M.D. 

Clinical  Instructor,  Department  of  Neurology,  Cornell  Uni- 
versity Medical  School,  New  York. 
Larkin,  John  H.,  M.D. 

Professor  of  Pathology,  Columbia  University,  New  York. 
Loewe,  Leo,  M.D. 

Research  Fellow,  Mt.  Sinai  Hospital,  New  York; 

Adjunct    Attending    Physician    in    Medicine,    Beth    Moses 

Hospital,  Brooklyn,  N.  Y. 
McConnell,  John  W.,  M.D. 

Associate  Professor  of  Neurology  in  the  Graduate  School  of 

Medicine,  University  of  Pennsylvania,  Philadelphia. 
Neustaedter,  Marcus,  M.D. 

Assistant  Attending  Neurologist,  City  Hospital,  New  York; 

Chief,  Neurological  Division,  Stuy vesant  Polyclinic,  New  York. 


LIST  OF  CONTRIBUTORS  xi 

Pardee,  Irving  H.,  M.D. 

Instructor  in  Neurology,  Columbia  University,  New  York; 

Associate  Physician,  Neurological  Institute,  New  York. 
Pike,  Frank  H.,  Ph.D. 

Associate    Professor    of   Physiology,    Columbia    University, 

New  York. 
Riley,  Henry  A.,  M.D. 

Associate  in  Neurology,  Columbia  University,  New  York; 

Assistant  Professor  of  Neurology,  New  York  Post-Graduate 

Medical  School  and  Hospital. 
Spiller,  William  G.,  M.D. 

Professor     of     Neurology,      University     of     Pennsylvania, 

Philadelphia. 
Stephenson,  Junius  W.,  M.D. 

Clinical  Instructor  in  Neurology,  Cornell  University  Medical 

School,  New  York. 
Strauss,  Israel,  M.D. 

Associate  Neurologist  and  Associate  in  Neuropathology,  Mt. 

Sinai  Hospital,  New  York. 
Thalhimer,  William  M.,  M.D. 

Director  of  Laboratories,  Columbia  Hospital,  Milwaukee. 
Tilney,  Frederick,  M.D. 

Professor  of  Neurology,  Columbia  University,  New  York. 
Timme,  Walter,  M.D. 

Attending  Neurologist,  Neurological  Institute,  New  York. 
Wechsler,  Israel  S.,  M.D. 

Associate  in  Neurology,  Columbia  University,  New  York. 
Wynne,  Shirley  W.,  M.D. 

Chief,    Division    of    Statistical    Research,    Department    of 

Health,  New  York. 
Zabriskie,  Edwin  Garvin,  M.D. 

Attending  Neurologist,  Neurological  Institute,  New  York. 


CONTENTS 

Chapter  Page 

Preface xv 

Introduction xvn 

I.  General  and  Historical  Considerations,  Incidence, 

Etiology  and  Pathogenesis •    •    •        l 

1 1 .  Symptomatology  :  Symptoms  Referable  to  the  Brain.     2 1 

III.  Symptomatology  :  Symptoms  Referable  to  the  Spinal 

Cord  and  Peripheral  Nerves 7 1 

IV.  Symptomatology:  Psychotic      Manifestations      of 

Epidemic  Encephalitis 103 

V.  Diagnosis,  Course  and  Prognosis;  Late  Results.    .    123 

VI.  Morbid   Anatomy:    Pathology   of   the   Brain   and 

Spinal  Cord;  Lesions  Outside  the  Nervous  System  158 

VII.  Bacteriology  and  Animal  Experimentation; 
Further  Studies  in  Pathogenesis,  Immunology 
and  Physiological  Functioning 197 


xiu 


PREFACE 

During  the  preparation  of  this  volume  for  publication 
there  was  considerable  discussion  by  members  of  the  Publica- 
tion Committee  as  to  the  best  way  of  presenting  the  material 
which  it  contains.  It  was  felt  that  a  formal  report  of  papers 
and  transactions  of  the  society  would  be  less  readable  than 
the  present  form  of  presentation.  In  preparing  the  material 
the  endeavor  was  made  to  harmonize  two  conflicting  aims. 
It  was  felt  that  each  contributor  should  be  credited  with 
all  the  facts  which  he  had  established,  and  at  the  same 
time  it  was  thought  unwise  to  include  duplicate  reports 
of  work  by  different  investigators.  As  a  result,  the  Com- 
mittee found  it  necessary  to  publish  only  such  material 
submitted  by  a  given  contributor  as  had  not  already  been 
submitted  by  another.  This  naturally  led  to  the  deletion 
of  parts  of  contributions.  It  should  be  appreciated  by  both 
contributors  and  readers  that  this  was  done  solely  in  order 
to  avoid  duplication  of  material,  and  not  because  of  lack  of 
excellence  of  any  parts  of  the  contributions  received. 

A  further  object  of  the  Publication  Committee  has  been  to 
allow  no  contribution,  either  in  the  written  report  of  inves- 
tigators or  brought  out  in  discussion,  to  go  unrecorded. 
For  this  reason  all  questions  of  clinical  bearing  submitted 
by  the  Committee  and  answered  by  contributors,  are  in- 
cluded in  the  text. 

The  Committee  wishes  to  take  this  occasion  to  express  its 
thanks  to  contributors  to  the  volume  for  the  detailed  and 
painstaking  studies  which  they  have  made  and  reported 
in  their  abstracts.  In  preparing  the  material  for  publica- 
tion the  members  of  the  Organization  and  Programme 
Committees  of  the  Association,  after  going  over  the  various 
articles,  recommended  the  above  outline  of  publication  to  the 

xv 


XVI 


PREFACE 


President.  This  outline  the  President  approved,  and  there- 
upon assigned  the  various  sections  to  different  members  of 
these  Committees  for  editing.  In  succeeding  volumes  it  may 
be  found  desirable  to  alter  or  modify  this  mode  of  presenta- 
tion. In  the  case  of  this  volume,  blame  for  certain  of  its  fail- 
ures or  praise  for  what  excellence  it  may  possess  in  the  way 
of  presentation  should  be  distributed  among  the  various 
members  of  these  Committees  of  the  Association. 

P.    B. 

New  York, 
September,  192 1. 


INTRODUCTION  i 

A  new  organized  effort,  a  new  association,  operating 
along  untried  lines,  has  been  suggested  to  you  in  the  belief 
that  it  might  have  as  a  result  the  scientific  advance  of 
neurology  and  psychiatry. 

From  the  outset  the  proposal  met  with  your  hearty 
endorsement;  you  have  brushed  aside  the  misgivings  which, 
nowadays,  assail  all  of  us  when  anything  to  add  to  our 
labors  is  proposed;  you  have  done  this  in  the  belief  that  what 
we  are  going  to  do  now  will  bring  substantial  return  to  our 
science. 

Those  of  us  who  conceived  and  nurtured  the  idea  wish, 
first  of  all,  to  express  gratitude  for  your  immediate  and 
hearty  support.  Time  will  show,  we  believe,  that  your  faith 
has  not  been  misplaced,  and  that  the  new  association  will 
bring  us  into  closer  relationship,  always  in  the  interest  of 
our  life's  work. 

The  present  era  of  turmoil  exerts  its  baneful  disintegrative 
influence  upon  all  educational  and  scientific  advance.  If  in 
medical  research  this  debasement  were  limited  to  a  diminu- 
tion of  output,  the  matter  would  be  of  no  special  concern,  for 
it  would  allow  time  for  a  criticism  and  assimilation  of  much 
that  had  been  presented  heretofore.  But  unfortunately, 
the  deficiency  does  not  show  itself  in  lack  of  production; 
for  never  before  were  there  as  many  medical  journals  as  at 
the  present  time;  never  before  were  the  mail  boxes  of  medical 
editors  more  crowded;  and  it  must  be  added,  the  scientific 
value  of  the  articles  offered  seems  to  be  in  inverse  ratio  to 
their  number.  The  amount   of  necessary  reading  entailed 

1  Presidential  address  by  Dr.  Walter  Timme  delivered  at  the  opening  of 
the  first  meeting  of  the  Association  for  Research  in  Nervous  and  Mental 
Diseases,  New  York,  December  28,  1920. 

xvii 


xviii  INTRODUCTION 

by  this  enormous  output  in  a  vast  number  of  scattered 
publications  becomes  a  serious  matter,  even  if  only  as  con- 
cerns time.  Time  expenditures  can  be  made  only  out  of  a 
limited  capital,  of  which  inevitable  subtractions  make 
a  rapidly  diminishing  fund.  The  burning  question  of  the 
times  is  the  intensive  use  of  the  minute.  How  shall  we  econo- 
mize our  time-energy  unit?  And  then,  how  shall  we  best 
use  it? 

Specialization  has  seemed  to  solve  partially  our  problem. 
But  more  and  more  is  the  realization  driven  home  that 
specialization,  far  from  becoming  narrower  must  be  planned 
in  accordance  with  its  obligations  to  medical  science  as  a 
whole,  and  not  exclusively  to  the  clinic  and  laboratory.  It 
must  consider  not  only  itself  but  also  the  sociological  and 
industrial  conditions  of  our  environment.  Thus  viewed, 
specialization  becomes  universalization.  In  no  field  is  this 
more  in  evidence  than  in  neurology  and  psychiatry. 

The  neurology  of  a  few  years  ago  was  content  and  com- 
placent with  a  bald  diagnosis  of  some  disease, — let  us 
say,  for  example,  lead  polyneuritis.  The  diagnosis  with  its 
prescribed  treatment  was  all  there  was  to  it.  But  it  is  now 
glaringly  evident  that  we  owe  a  duty  to  the  community, 
commensurate  with  that  which  has  brought  about  compul- 
sory vaccination.  This  duty  requires  us  to  define,  in  the 
first  place,  the  safeguards  to  be  erected  for  the  protection 
of  our  fellows;  we  must  interest  ourselves  further  and  inquire, 
Why  should  lead  have  singled  out  this  particular  individual? 
Is  it  a  matter  with  him  of  less  resistance  to  that  particular 
poison,  carelessness  in  its  use,  or  both.  Are  other  co-workers 
similarly  affected  or  likely  to  be?  What  methods  are  pro- 
vided by  the  plant  to  protect  the  workers?  Are  they  ade- 
quate? Is  there  supervision?  Does  the  state  take  cognizance 
of  laxity  in  the  enforcement  of  proper  laws  for  the  safety  of 
lead  workers  in  all  plants,  and  are  there  proper  state  laws  to 
insure  safety  to  lead  workers?  What  is  the  loss  to  the  com- 
munity of  an  improperly  regulated  industry?  The  answer  to 
these  questions  implies  an  active  and  widespread  investiga- 


INTRODUCTION  xix 

tion  undertaken  to  improve  medico-sociological  conditions. 
In  England,  for  instance,  Sir  Thomas  Oliver  has  accom- 
plished results  in  this  particular  field  that  make  him  a  public 
benefactor.  We  cannot  escape  our  responsibility  here. 

Our  psychiatry  would  be  poor  indeed  if,  for  example,  it 
stopped  with  the  discovery  that  the  cause  of  paresis  is 
syphilis.  It  is  its  duty  to  go  into  the  sociological  problems 
involved  in  the  dissemination  of  syphilis  and  attempt  to 
solve  them.  These  problems  are  apparent  and  need  not 
particularly  be  detailed  now.  The  point  I  desire  to  make  is 
that  our  specialization  must  be  of  universal  application. 

In  practically  all  our  work  a  similar  situation  exists. 
Multitudinous  problems  confront  us.  The  time  element,  the 
energy  factor,  the  bread  and  butter  necessity- — to  say  nothing 
of  the  opposition  that  is  always  encountered — are  almost 
beyond  encompassment.  Shall  we  deny  the  responsibility? 
We  cannot.  Ours  is  the  problem;  ours  as  well  must  be  the 
quest  for  the  solution.  The  largest  factors  in  the  solution  are 
the  energy  and  time  elements. 

I  think  you  will  agree  with  me  that  much  that  we  do 
as  individuals  in  our  chosen  field  is  opportunistic.  By  this 
I  mean  that  if  in  the  course  of  our  work  an  interesting  case, 
or  a  series  of  such,  arises  or  an  apparently  new  symptom  is 
discovered,  or  a  new  method  of  enquiry  suggests  itself,  we 
make  a  memorandum,  and,  when  time  allows,  we  expand 
upon  it  and  publish  a  paper.  Such  publications  fill  the  medi- 
cal journals.  They  are  discrete,  non-related,  not  properly 
balanced,  all  too  often  redundant  and  verbose;  many  are 
mere  duplications  and  some  few  are  reliable.  There  is  a 
multiplicity  of  single,  uncritical  clinical  observations  to  one 
of  well-founded  merit.  And  the  number  of  theories  of  disease 
advanced  on  the  flimsiest  of  groundwork  makes  the  reading 
of  medical  journals  much  like  attendance  upon  the  moving 
picture:  logical  sequence  is  thrown  to  the  winds  so  long  as 
weird  contrasts  and  rapidity  of  change  dominate  the  story. 
But  we  have  a  ready  excuse.  When  our  work  shows  incoordi- 
nation of  thought  and  plan,  limitation  of  scope,  slight  and 


xx  INTRODUCTION 

uncertain  conclusions,  and,  as  a  result  we  are  accused  of 
superficiality,  we  usually  fall  back  upon  the  statement  that 
medicine  in  America  cannot  properly  advance  until  our 
clinical  observations  and  deductions  are  checked  up,  and 
more  post-mortem  material  is  made  available.  In  spite  of 
the  truth  which  such  an  apology  holds,  I  believe  our  position 
would  be  better  if  we  decried  less  our  lack  of  such  oppor- 
tunity, and  bent  our  energy  more  to  intensive  ante-mortem 
study.  One  thing  we  Americans  possess,  and  that  is  a 
vigorous  initiative  for  combined  effort.  Let  us  make  applica- 
tion of  this  quality  to  our  present  problems.  Such  combina- 
tion of  effort,  to  be  successful,  requires  several  conditions: 
First,  a  goal  to  be  attained;  second,  a  coordination  of  the 
forces  available;  third,  a  proper  supervision  and  control  to 
prevent  overlapping  or  undermanning.  If  these  factors 
can  be  furnished,  results  will  follow;  there  will  be  concerted, 
coordinate  action  by  a  group  of  men  on  a  definite  problem 
without  loss  of  time  or  duplication  of  work.  It  will  reduce  the 
amount  of  reading  necessary  while  enhancing  the  interest; 
there  will  be  one  story  in  several  chapters,  with  a  conclusion. 

It  is  in  accordance  with  these  principles  that  our  present 
Association  for  Research  in  Nervous  and  Mental  Diseases 
was  founded. 

Let  us  understand  at  the  outset  that  this  Association  is  not 
merely  one  more  society  added  to  innumerable  others  for  the 
bedevilment  of  the  medical  fraternity.  It  is  congenitally 
different  and  will  functionate  in  a  manner  quite  its  own. 
The  discussions  with  their  tergiversations  incidental  to 
large  meetings  will  retire  before  sounder  methods  of  getting 
at  truth. 

To  outline  briefly  the  functions  of  the  organization  which 
we  have  brought  into  being,  to  declare  its  aims  and  purposes, 
and  to  show  that  by  its  existence  many  of  the  evils  before 
enumerated  and  which  automatically  are  increasing,  will 
be  lessened  or  eradicated,  is  my  chief  function  today. 

Foremost  of  all,  the  coordination  of  efforts  in  one  direc- 
tion, following  a'  plan  outlined  in  advance  with  a  definite 


INTRODUCTION  xxi 

object  in  view  is  the  main  principle  underlying  our  proposed 
activities.  A  group  of  men  of  experience  in  neurology  and 
psychiatry  elected  by  the  members  of  the  Association,  after 
due  and  mature  deliberation,  decide  upon  an  object  of 
research — some  disease  entity — which  has  ever  balked  and 
baffled  us.  The  choice  of  the  subject  is  made  one  or  possibly 
two  years  in  advance  of  the  date  set  for  its  intensive  dis- 
cussion and  workers  in  all  fields  of  medicine  are  urged  to 
engage  in  the  investigation  in  their  own  special  lines.  Lab- 
oratory workers,  pathologists,  physiologists  and  clinicians 
set  to  work  along  definite  paths,  each  group  in  its  own  way 
attacking  the  problem.  The  material  for  them  to  study  is 
furnished  by  all  physicians  of  the  Association  and  by  others 
interested,  and  due  credit  is  given  for  such  assistance. 
In  this  way,  practically  all  cases  of  the  disease  in  the  territory 
covered  by  the  Association  will  come  under  the  observation 
of  those  studying  the  problem.  At  once  the  multitudinous, 
incoordinated,  single  observations  which  fill  our  medical 
journals  become  superfluous;  redundancy  and  reduplication 
fade  away.  What  otherwise  would  have  taken  years  to 
accomplish  by  the  most  painstaking  efforts  and  collaboration 
becomes  a  matter  of  a  few  months.  When,  finally,  the  day  for 
a  casting  up  of  results  of  this  coordinated  and  intensive  study 
arrives,  the  papers  embodying  the  results  of  the  individual 
researches  are  carefully  studied  by  the  members  of  the  Com- 
mission; and  when  presented  to  the  Association  by  them, 
the  proponents  of  the  various  theses  are  interrogated  as  to 
their  work,  their  conclusions,  and  on  any  details  that  may 
still  need  elucidation.  At  the  conclusion  of  the  meeting,  the 
Commission  will  prepare  for  publication  all  the  matter 
presented  to  it  in  coordinated,  sequential  form,  together  with 
its  own  comments  as  a  commission,  and  issue  a  volume  to  be 
distributed  to  the  members  of  the  Association.  Each  of  us 
will  then  be  in  possession  of  all  that  is  known  about  the 
disease  in  question  to  the  last  minute,  almost  up  to  the 
"time  of  going  to  press."  In  a  comparatively  short  period  of 
time,   a   series  of  such   volumes   will   constitute  American 


xxii  INTRODUCTION 

archives  of  our  specialty  of  surpassing  completeness.  Re- 
search thereafter  will  need  to  begin  only  with  the  latest 
American  archives  on  the  subject,  and  the  weary  task  of 
looking  up  the  literature,  which  is  as  far  as  many  intrepid 
but  time-limited  souls  get,  will  be  a  thing  of  a  revered  past. 

You  should  know  that  the  plan  of  the  organization  was 
evolved  only  by  the  very  assiduous  constructive  work  of  the 
members  of  the  various  organization  committees,  who  gave 
generously  of  their  time  and  advice  during  the  past  year 
and  without  whose  initiative  and  support  there  could  have 
arisen  no  such  association  as  ours.  I  violate  no  confidence 
in  stating  that  the  brunt  of  the  work  and  responsibility  fell 
upon  our  devoted  friends,  Drs.  Charles  L.  Dana,  Frederick 
Tilney  and  Foster  Kennedy,  and  that  whatever  merit  there 
may  be  found  is  due  in  the  largest  part  to  them. 

I  believe  that  little  analysis  will  be  necessary  to  demon- 
strate the  enormous  advantage  accruing  to  all  of  us,  and 
to  neuropsychiatric  science  in  particular,  by  the  applica- 
tion of  the  methods,  the  trial  of  which  begins  today.  There 
will,  doubtless,  be  many  faults  uncovered;  many  changes  in 
procedure  will  become  necessary  before  a  fairly  perfected 
plan  will  come  out  of  it  all;  but  with  your  kindly  cooperation 
and  constructive  criticism,  I  see  arising  out  of  this  modest 
beginning  a  powerful  force  for  good,  a  unified  and  inspired 
ail-American  group  of  neurologists  and  psychiatrists,  whose 
basic  aim  is  the  advance  of  American  Medicine. 


Chapter  I 

GENERAL   AND    HISTORICAL    CONSIDERATIONS, 
INCIDENCE,  ETIOLOGY  AND  PATHOGENESIS 

THIS  first  chapter  deals  with  certain  general  considera- 
tions of  epidemic  encephalitis.  The  general  character- 
istics of  the  lesions  and  the  extent  of  our  most  recent 
knowledge  of  the  disease  are  discussed  by  Dr.  Lewellys  F. 
Barker  of  Baltimore.  Dr.  Shirley  W.  Wynne,  of  the  Health 
Department  of  New  York  City,  has  made  a  contribution  to 
its  epidemiology,  making  use  of  the  data  available  to  the 
Health  Department.  Dr.  Israel  S.  Wechsler  has  collected 
statistical  data  from  hospital  reports,  reports  of  physicians 
and  other  sources,  covering  both  this  country  and  Canada. 
A  summary  of  the  observations  of  Dr.  William  M.  Thal- 
himer  of  Milwaukee,  Dr.  Leo  Loewe  and  Dr.  Israel  Strauss  of 
New  York  City  on  pathogenesis  concludes  the  reports  of  this 
chapter.  A  more  detailed  report  in  reference  to  pathogenesis, 
including  animal  experimentation,  is  presented  by  these 
writers,  as  well  as  by  several  others,  in  Chapter  VII  of  this 
volume. 

General  Considerations  (Lewellys  F.  Barker). 
Since  von  Economo  in  191 7  described  as  "lethargic  encepha- 
litis" an  epidemic  disease  in  which  the  diagnostic  criteria 
consisted  of  the  triad — somnolence,  ophthalmoplegia,  and 
profound  asthenia,  our  knowledge  of  the  symptomatology 
and  pathology  of  acute,  subacute  and  chronic  nonsuppura- 
tive inflammations  of  the  nervous  system  has  undergone 
rapid  and  prodigious  augmentation.  The  spread  of  the 
disease  in  epidemic  form  over  the  whole  civilized  world 
and   the   occurrence   of  successive   outbreaks   in   modified 


2  ACUTE  EPIDEMIC  ENCEPHALITIS 

form  in  each  of  several  countries  have  given  an  unusual 
opportunity  to  clinical  and  pathological  investigators  for 
the  exact  study  of  this  remarkable  malady  under  the  most 
different  conditions.  It  is  but  little  wonder  that  progress 
has  been  made  by  leaps  and  by  bounds;  and  though  we  are 
still  ignorant  of  a  vast  deal  that  we  should  like  to  know,  the 
conceptions  of  the  disease  held  today  are  very  far  removed 
from  those  of  19 17.  A  great  variety  of  states,  which  at  that 
time  would  not  have  been  classified  under  the  rubric  of  this 
disease,  are  now  immediately  recognized  as  belonging  there 
by  all  familiar  with  the  malady  and  the  bibliography. 

The  number  and  the  variety  of  symptoms  which  may  be 
presented  by  patients  suffering  from  this  infection,  and 
the  diverse  combinations  and  sequences  of  the  symptoms 
in  single  cases,  are  striking  features  of  the  disease.  A  French 
writer,  C.  Achard,  has  well  expressed  it,  "the  disease  is 
polymorphous  and  acyclic."  It  occurs  in  an  endless  number 
of  clinical  forms,  and  though  in  most  cases  the  course  of  the 
malady  is  divisible  into  several  stages,  the  serial  sequence  of 
these  stages  may  be  very  different  in  different  epidemics 
and  even  in  single  cases  in  the  same  epidemic.  The  variegated 
symptomatology,  the  great  diversity  of  syndromes  met  with, 
the  apparent  absence  of  any  constant  chronology  in  the 
development  of  the  syndromes,  and  the  aping  by  this  malady 
of  almost  every  well-known  and  well-defined  neurological 
symptom-complex,  have  been  responsible  for  many  mistakes 
in  diagnosis  and  have  caused  even  some  of  the  best-informed 
students  of  the  disease  almost  to  despair  of  creating  any 
sort  of  order  out  of  the  clinical  chaos  presented. 

That  there  is,  however,  a  fundamental  unity  in  this  per- 
plexing diversity,  we  are  now  fairly  certain.  We  have  to  deal 
with  a  single  disease,  due  doubtless  to  a  specific  virus,  in 
which  the  clinical  manifestations  are  very  diverse,  owing  to 
differences  in  intensity  of  the  virus  and  its  toxins  and  to 
variations  in  the  localization  of  the  multiple  lesions  pro- 
duced. The  epidemic  character  of  the  malady,  a  prevalence  so 
wide  that  an  acquaintance  with  it  has  become  possible  to 


GENERAL  AND  HISTORICAL  CONSIDERATIONS      3 

all  consulting  internists,  neurologists  and  ophthalmologists, 
as  well  as  to  large  numbers  of  other  general  and  special 
practitioners,  the  characteristic  pathological  histology  of 
the  widely  disseminated  lesions  in  the  nervous  system,  the 
combinations  and  overlappings  in  certain  cases  of  two  or 
more  syndromes  that  are  often  met  with  singly  in  others, 
have  placed  beyond  doubt  the  fact  that  we,  despite  the  mul- 
tiplicity of  symptoms,  are  dealing  with  a  unitary  disease  de- 
pendent for  its  causation  upon  some  specific  infectious  agent. 

Epidemiology  (Shirley  W.  Wynne).  Our  knowledge  of 
the  epidemiology  of  encephalitis  is  very  meager,  but  it  may 
serve  a  useful  purpose  if  we  briefly  set  forth  those  facts 
which  we  possess.  It  is  agreed  that  it  is  an  acute  disease; 
that  it  affects  the  nervous  system,  and  that  its  outstanding 
symptom  is  lethargy.  It  occurs  in  epidemic  form,  and  most 
observers  are  agreed  that  during  the  last  two  hundred  years 
we  have  had  several  epidemics  of  this  disease.  Crookshank, 
in  a  very  interesting  article  in  the  Boston  Medical  and  Surgical 
Journal,1  attempts  to  trace  the  disease  back  to  the  time  of 
Hippocrates.  He  calls  attention  to  the  fact  that  during  the 
last  four  hundred  and  fifty  years  there  have  been  a  number 
of  epidemics  of  the  disease  in  many  countries  of  Europe, 
but  that  in  these  epidemics  there  is  apparently  a  confusion 
of  encephalitis,  poliomyelitis  and  influenza.  The  one  out- 
standing fact  in  Crookshank's  history  of  this  disease  which,  as 
he  tells  us,  was  described  under  different  names  and  attributed 
to  different  causes,  in  the  different  countries  in  which  it 
occurred,  is  that  the  diseases  which  he  thinks  were  enceph- 
alitis, poliomyelitis  and  influenza  bore  a  resemblance  in  their 
symptomatology  and  occurred  more  or  less  simultaneously. 
There  was  in  1712  a  well-defined  outbreak  of  sleeping 
sickness  in  Germany,  which  was  attributed  to  the  eating  of 
poisonous  food,  and  it  is  interesting  to  note  that  food  poison- 
ing was  again  advanced  as  the  cause  of  this  disease  in  the 
last  epidemic.  The  present  epidemic  started  in  Vienna  in  the 

1  Crookshank,  F.  G.   A  note   on  the  history  of  epidemic  encephalomyelitis. 
Boston  M.  &  S.  J.,  January  8,  1920,  clxxxii,  34. 


4  ACUTE  EPIDEMIC  ENCEPHALITIS 

winter  of  191 6  and  191 7.  In  19 18  it  appeared  in  England 
and  its  greatest  incidence  was  in  the  spring  of  that  year. 
In  March,  1919,  the  first  cases  appeared  in  New  York, 
at  least  these  were  the  first  to  be  officially  reported  to  the 
Health  Department.  From  that  time  until  the  present,  cases 
have  occurred  from  day  to  day.  During  1919  there  were 
46  deaths  reported  from  this  disease  in  New  York  City. 
During  the  first  eleven  months  of  1920  there  have  been  228 


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Fig.  1.     Monthly  mortality,  1920,  in  City  of  New  York. 


deaths  reported.  In  January,  1920,  there  were  12  deaths; 
in  February,  53;  in  March,  57;  in  April,  29;  May,  30;  June, 
1 3 ;  July,  1 1 ;  and  after  that  the  rate  fell  to  6  deaths  a  month 
during  the  remaining  months  until  the  first  of  December. 
The  deaths  were  distributed  throughout  all  the  boroughs 
of  the  city,  the  largest  number  of  cases  being  reported,  of 
course,  from  the  most  populous  boroughs. 

The  Public  Health  Reports  show  cases  reported  from 
California,  from  Florida  and  from  Maine,  during  the  same 
week,  denoting  a  widespread  distribution.  But  we  have  been 
unable  to  trace  any  definite  path  that  the  epidemic  followed, 
as  we  did  in  the  epidemic  of  influenza. 

Three  theories  have  been  advanced  as  to  the  cause  of  the 


GENERAL  AND  HISTORICAL  CONSIDERATIONS     5 

disease  during  the  last  year  and  a  half:  (1)  That  it  was  due  to 
food  poisoning,  a  theory  quickly  disproved.  (2)  That  it  is  a 
mutated  form  of  influenza.  Some  still  cling  to  this  idea  and 
advance  as  the  reason  for  this  theory  the  fact  that  both 
diseases  occurred  about  the  same  time.  (3)  That  encephalitis 
and  influenza  were  very  widespread,  and  roughly  followed 
the  same  course  in  traveling  from  one  country  to  another, 
the  proponents  of  this  theory  also  stating  that  influenza 
has  in  different  phases  of  the  same  epidemic  affected  different 
tissues  of  the  body:  thus  at  one  time  the  respiratory  tract, 
at  another  the  gastro-intestinal  tract,  and  at  still  another 
the  nervous  system.  There  has  also  been  a  striking  similarity 
in  the  age  distribution  of  encephalitis  and  influenza. 

On  the  other  hand,  the  epidemic  of  encephalitis  started 
in  Vienna  in  the  winter  of  19 16  and  191 7,  before  the  outbreak 
of  influenza  had  made  its  appearance.  In  England  the  time  of 
the  epidemics  of  encephalitis  and  of  influenza  more  nearly 
coincide.  In  the  United  States  the  epidemic  of  encephalitis 
has  followed  more  closely  the  epidemic  of  influenza.  Further- 
more, in  none  of  the  series  of  cases  that  has  been  studied 
have  we  been  able  to  secure  a  sufficiently  large  number  of 
histories  of  previous  attacks  of  influenza  or  of  exposure  to 
influenza  to  justify  the  belief  that  there  was  any  connection 
between  the  two  diseases.  Dr.  Louis  I.  Harris,  of  the  New 
York  Health  Department,  studied  63  cases,  and  of  these  16 
gave  a  history  of  a  previous  attack  of  influenza,  14  gave  a 
definite  history  of  exposure  to  influenza,  and  40  gave  no 
history  of  a  previous  attack  or  of  exposure  to  influenza. 
In  the  3  remaining  cases  the  histories  were  unsatisfactory 
and  were  disregarded.  Similarly,  in  117  cases  of  encephalitis 
there  were  but  17  cases  which  gave  a  history  of  influenza. 
Our  experience  during  the  last  epidemic  was  that  there  were 
multiple  or  secondary  cases  of  influenza  in  almost  every 
family  where  encephalitis  occurred.  So  far  reported,  there 
has  been  only  one  instance  where  there  has  been  a  secondary 
case  of  encephalitis  lethargica.  Indeed,  in  going  over  the 
report  of  the  Committee  that  studied  the  epidemic  in  Eng- 


6  ACUTE  EPIDEMIC  ENCEPHALITIS 

land,  there  is  related  the  case  of  a  boy  whom  they  observed 
sleeping  in  the  same  bed  with  four  other  children  of  the 
family.  The  boy  died,  but  none  of  the  other  children  had 
the  disease  or  showed  any  symptoms  of  it.  This  would 
seem  to  indicate  that  there  was  no  relation — no  direct 
relation — between  encephalitis  and  influenza.  The  influenza 
epidemic  or  pandemic,  as  Flexner  states,  perhaps  served 
only  to  prepare  the  soil  for  the  epidemic  of  encephalitis  by 
lowering  the  resistance  of  the  communities  invaded. 

As  to  poliomyelitis,  it  has  been  said  that  this  disease 
was  similar  to  encephalitis  and  was  caused  by  the  same  agent, 
because  both  diseases  attack  the  central  nervous  system, 
both  occur  in  epidemic  form,  and  because,  as  some  authors 
have  attempted  to  point  out — Crookshank  notably — 
there  was  a  chronological  relation  between  the  epidemics  of 
poliomyelitis  and  encephalitis.  On  the  other  hand,  there  are 
many  differences  in  the  epidemiology  of  the  two  diseases. 
Encephalitis  is  distributed  throughout  all  age  groups.  Cases 
have  been  found  in  children  under  one  year  of  age  and  in 
persons  over  seventy-five  years  of  age.  The  greatest  inci- 
dence, however,  is  during  adult  life,  particularly  between 
the  ages  of  twenty-five  and  forty-five.  Poliomyelitis,  on  the 
other  hand,  is  found  for  the  most  part  among  children,  and 
during  the  epidemic  of  191 6  in  New  York  City  over  90  per 
cent  of  the  cases  of  poliomyelitis  occurred  among  children 
under  ten  years  of  age. 

The  seasonal  occurrence  of  the  two  diseases  also  differs. 
Encephalitis  occurs  in  all  seasons  of  the  year.  Deaths  were 
reported  during  every  month  of  1920  up  to  December  1st, 
but  the  greatest  incidence  was  in  February  and  March. 
Poliomyelitis,  on  the  other  hand,  occurs  most  frequently  in 
warm  weather.  Another  point  is  that  if  both  diseases  were 
due  to  the  same  organism,  we  should  expect  to  find  frank 
cases  of  poliomyelitis  during  epidemics  '  of  encephalitis 
and  vice  versa.  This  has  not  been  the  case/[The  Committee 
appointed  to  study  the  disease  in  England  observed  in 
certain  communities  the  occurrence  of  encephalitis  where  no 


GENERAL  AND  HISTORICAL  CONSIDERATIONS     7 

cases  of  poliomyelitis  were  reported,  and  the  occurrence  of 
poliomyelitis  where  no  cases  of  encephalitis  were  reported. 
In  the  largest  centers  of  population,  cases  of  both  diseases 
were  found  simultaneously,  but  that  is  true  of  almost  all 
the  acute  contagious  diseases.  In  New  York  City  we  have 
cases  of  diphtheria,  scarlet  fever,  and  measles  occurring 
at  the  same  time. 

The  following  questions  submitted  to  Dr.  Wynne  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Williams:  Have  you  studied  the  bacteriology  of  alleged 
cases  of  influenza  preceding  or  in  contact  with  cases  subsequently 
shown  to  be  encephalitis  of  specific  etiology? 

Dr.  Wynne:  No  sir. 

Dr.  Williams:  Are  you  satisfied  that  many  alleged  influenza 
cases  are  not  abortive  encephalitis  forms  first? 

Dr.  Wynne:  I  think  they  are  not.  I  don't  think  it  is  within 
the  province  of  our  office  to  pass  on  that;  it  is  a  question  of 
diagnosis. 

Dr.  Dana:  How  correct  do  you  suppose  is  the  diagnosis  of 
deaths  from  encephalitis?  You  say  you  had  200  odd  cases  in 
1920.  Do  you  suppose  most  of  the  diagnoses  are  correct? 

Dr.  Wynne:  That  is  a  rather  difficult  question  to  answer. 
You  realize  what  difficulty  the  statistical  office  has  in  determining 
whether  the  causes  of  death  reported  are  reliable.  In  this  instance 
we  have  checked  up  a  number  of  diagnoses  by  sending  out  our 
diagnostician,  and  I  think  that  the  large  proportion  of  these 
deaths  have  been  true  cases  of  encephalitis.  Furthermore,  the 
majority  of  these  deaths  have  been  reported  from  hospitals  where 
the  opportunities  for  diagnosing  them  correctly  have  been  greatest. 
We  have  not  had  many  cases  reported  in  general  practice  from 
private  homes. 

Dr.  Dana:  How  does  the  mortality  rate  compare  with  that  in 
other  cities  in  this  country?  Chicago  and  Philadelphia? 

Dr.  Wynne:  I  have  been  unable  to  get  any  information  along 
that  line.  I  referred  to  the  Public  Health  Service  as  the  quickest 
means,  and  they  informed  me  that  the  records  are  far  from  com- 
plete. The  cases  have  not  been  reported  promptly  but  have  been 


8  ACUTE  EPIDEMIC  ENCEPHALITIS 

scattered  throughout  the  year,  so  that  I  am  unable  to  answer  that 
question  at  this  time. 

Dr.  Skoog:  Have  you  a  record  of  verification  by  autopsy  of  the 
fatal  cases? 

Dr.  Wynne:  There  was  no  way  of  getting  that  on  the  short 
time  I  was  given  to  prepare  this  little  paper,  because  the  method 
of  tabulating  in  statistical  offices  does  not  show  on  the  tabulating 
card  the  fact  that  the  diagnosis  has  been  verified  by  autopsy  or 
other  methods.  It  would  require  a  return  to  the  original  method 
and  taking  the  matter  up  with  the  physician  who  reported 
the  case. 

Dr.  Patrick:  May  I  ask  Dr.  Wynne  how,  as  he  expresses  it, 
the  influenza  prepares  the  soil  for  encephalitis  if  there  is  no  direct 
relation? 

Dr.  Wynne:  Rather  by  weakening  the  resistance  of  the  persons 
in  the  community  which  has  been  invaded  by  an  epidemic. 

Dr.  Patrick:  That  would  be  assuming  that  their  resistance 
has  been  diminished  although  they  have  not  had  influenza. 

Dr.  Wynne:  I  realize  there  is  a  school  that  adheres  to  the 
belief  that  the  susceptibility  of  the  individual  has  nothing  to  do 
with  the  infection;  that  it  is  due  entirely  to  the  virulence  of  the 
infecting  organism.  On  the  other  hand,  while  we  are  awaiting 
positive  proof  of  such  a  theory,  I  think  most  epidemiologists  are 
agreed  that  other  diseases,  especially  epidemic  diseases,  will 
lower  the  resistance  of  the  persons  in  the  community  to  another 
epidemic  disease,  and  it  was  on  that  ground  that  I  made  that 
remark.  I  find  in  going  over  the  literature  that  Flexner  felt  the 
same  way  about  it. 

Dr.  Patrick  :  I  don't  know  if  I  get  the  point  of  your  reply  or  if 
you  get  the  point  of  my  question,  but  I  gather  from  your  state- 
ments that  in  cases  of  encephalitis,  influenza  has  not  preceded  it 
in  the  individual.  How  then  does  it  follow  that  influenza  prepares 
the  soil  if  the  individuals  who  acquire  epidemic  encephalitis  have 
not  had  influenza? 

Dr.  Wynne:  Simply  by  lowering  the  resistance  of  all  the  people 
in  the  community.  Where  there  may  have  been  some  cases  not 
reported,  they  simply  served  as  a  means  of  passing  it  along  to  the 
others  who  came  down  with  the  disease. 

Dr.  Patrick:  Do  you  think  that  these  encephalitis  cases  should 
be  reportable  as  a  disease? 


GENERAL  AND  HISTORICAL  CONSIDERATIONS      9 

Dr.  Wynne:  That  is  a  question  which  it  is  not  fair  to  ask  me  to 
answer. 

A  Member:  What  is  your  total  percentage  of  mortality? 

Dr.  Wynne:  Among  the  cases  studied  the  mortality  was  40 
per  cent.  We  have  no  way  of  knowing  the  mortality  rate  for  the 
entire  city. 

Dr.  Sachs:  Isn't  it  true,  Dr.  Wynne,  that  at  the  time  of  an 
epidemic  the  diagnosis  of  the  disease  is  apt  to  be  made  just  as  often 
in  cases  not  really  definitely  established? 

Dr.  Wynne:  I  think  that  is  true  of  such  widespread  conditions 
as  influenza,  and  undoubtedly  during  the  influenza  epidemic  we 
had  deaths  reported  that  were  probably  not  from  influenza;  but 
in  a  disease  where  we  have  only  228  deaths  in  an  entire  year  out 
of  a  population  of  six  millions,  and  where  most  of  the  deaths  have 
occurred  in  institutions,  I  think  it  is  safe  to  say  that  the  percentage 
of  error  in  those  228  deaths  is  small. 

Dr.  Strauss:  Have  you  not  noticed  that  both  in  the  epidemics 
of  19 1 8-19 19  and  19 19-1920  as  the  epidemic  of  influenza  waned 
the  epidemic  of  encephalitis  began  to  reach  its  height? 

Dr.  Wynne:  The  first  phase  of  the  influenza  epidemic  was  in  the 
spring  of  1918;  the  second  heavy  phase  was  in  the  fall  of  1918.  In 
the  spring  of  19 19  our  first  cases  of  deaths  from  encephalitis  were 
reported.  During  that  year,  however,  there  were  only  46  deaths 
from  encephalitis  reported  in  the  city.  During  January,  1920, 
there  were  less  than  20,  in  February  there  were  54,  and  in  March 
there  were  over  50  deaths  reported  from  this  disease,  and  then  it 
began  to  wane  after  that  until  the  last  month  when  there  were  but 
6  deaths  reported.  Hence,  it  is  true  that  the  influenza  epidemic 
waned  before  the  cases  of  encephalitis  appeared  in  this  country, 
or  in  this  city  at  any  rate.  Abroad,  I  believe,  the  cases  of  encephalitis 
antedated  those  of  influenza.  In  France  and  England  the  period 
more  nearly  coincided. 

Dr.  Taylor:  Are  there  any  statistics  available  regarding  dis- 
tribution as  to  social  position, — that  people  living  in  salubrious 
surroundings  are  less  liable? 

Dr.  Wynne:  Apparently  not.  There  are  no  definite  statistics 
along  those  lines,  but  judging  from  distribution  by  nationalities 
and  occupations  in  the  city,  there  seems  to  be  little  difference. 

Dr.  Kennedy:  Dr.  Wynne,  your  death-rate  seemed  very  high. 
Is  it  not  possible  that  the  death-rate  seems  higher  to  a  public 


10 


ACUTE  EPIDEMIC  ENCEPHALITIS 


board  of  health  who  are  looking  at  marked  cases,  cases  which  are 
very  severe,  in  which  the  death  incidence  would  be  higher? 

Dr.  Wynne:  Those  cases  in  that  group  were  of  the  severe  type. 
The  milder  cases  had  not  been  reported,  and  therefore  were  not 
investigated. 

Dr.  Kennedy:  It  is  our  belief  that  jx)_per  cent  is  rather  high; 
I  think  there  were  a  good  many  minor  cases~  which  were  not 
reported  and  which  didn't  come  under  your  view. 

Dr.  Wynne:  Yes,  we  had  to  depend  upon  the  voluntary  reports 
of  physicians  to  send  us  in  the  questionnaire. 

Incidence  (Israel  S.  Wechsler).  The  statistical  data 
of  864  case  reports  were  studied.  Practically  every  part  of 
the  United  States,  as  well  as  Montreal,  Canada,  is  represented, 
although  more  than  half  of  the  records  came  from  New  York 
City.  Cases  from  clinics  and  dispensaries  were  purposely 
omitted,  since  many  of  them  had  previously  been  seen  in 
hospitals.  The  discrepancy  in  the  various  totals  is  due  to 
the  fact  that  in  a  few  instances  the  necessary  data  were  left 
out  in  the  records  submitted. 

Age.  The  youngest  cases  on  record  are  in  infants  of  four 
weeks.  There  were  3  such  cases.  One  occurred  in  an  infant  of 
six  weeks  and  1  in  one  of  seven  weeks.  The  oldest  case  re- 
corded is  that  of  a  man  of  eighty-four.  Evidently  no  age  was 
spared,  although  the  greatest  number  occurred  between 
twenty  and  fifty.  To  those  who  have  sought  to  correlate  epi- 
demic encephalitis  with  poliomyelitis  this  fact  is  of  some 
importance.  If  the  percentages  in  the  various  decades  were 
compared  with  the  percentages  of  the  population  of  the 
various  decades  it  will  be  seen  that  childhood  was  practically 
spared  and  even  adolescence  was  not  much  affected. 

Table  I 
age  incidence 


|  Below 

II     5 

6-io|  11-20 

21-30I31-40 

41-50  51-60  61-70 

Over 

70 

[  Total 

No. 

13 

37         136 

222     215 

140      72         23 

6 

864 

Per 
Cent. 

..5 

1 
4   1    15-7 

25. 7j     25 

16.2    8.3      2.8 

•7 

| 

100 

GENERAL  AND  HISTORICAL  CONSIDERATIONS    n 

Sex.  The  male  sex  was  affected  much  more  severely  than 
the  female.  There  were  522  males  and  342  females — a  per- 
centage of  60.5  to  39.5  or  a  ratio  of  almost  exactly  3  to  2. 
This  is  difficult  to  explain.  Greater  exposure  of  the  male 
sex  or  occupational  strain  may  possibly  be  held  to  account, 
but  the  suggestion  is  merely  speculative.  The  fact  itself, 
however,  is  sufficiently  interesting  and  worthy  of  note. 

Occupation.  Every  conceivable  occupation  was  repre- 
sented among  the  cases.  There  are  seventeen  physicians  in 
the  group,  almost  2  per  cent  of  the  total  number  of  cases. 
When  one  considers  that  the  total  number  of  physicians 
of  the  country  is  slightly  over  1/8  of  1  per  cent  of  the  whole 
population,  the  incidence  among  doctors  was  exceptionally 
high,  or  almost  16  times  as  frequent  as  among  the  average 
population.  Whether  this  fact  has  any  bearing  on  exposure 
or  infectivity  can  merely  be  conjectured.  Among  the  physi- 
cians were  two  hospital  interns. 

Nativity.  Of  860  cases  reported  upon  there  were  387 
natives  and  473  foreign  born,  that  is  45  per  cent  of  the  former 
and  55  per  cent  of  the  latter.  The  native  population  of  the 
country  in  general  and  even  that  of  New  York  City  exceeds 
greatly  the  foreign  population  and  yet  the  disease  incidence 
was  greater  in  the  latter.  This  fact  is  difficult  to  explain 
even  when  one  takes  into  consideration  the  high  incidence 
of  disease  among  adults  who  furnish  the  bulk  of  the  foreign 
population,  and  the  fact  that  most  of  the  cases  here  recorded 
came  from  New  York  City. 

Civil  Status.  There  were  300,  or  34.7  per  cent,  single 
patients,  491,  or  56.9  per  cent,  married  and  73,  or  8.4  per 
cent,  not  stated.  This  preponderance  of  the  married  over  the 
single  may  perhaps  be  explained  by  the  fact  that  most  of  the 
cases  (about  65  per  cent)  occurred  in  persons  over  twenty- 
five  years  of  age. 

Pregnancy.  There  are  records  of  twenty-two  pregnant 
women  who  had  encephalitis.  Two  of  these  aborted  and  one 
had  a  caesarian  section  done.  One  woman  was  delivered  in 
the   eighth   month   of  pregnancy,   both   mother  and   child 


12 


ACUTE  EPIDEMIC  ENCEPHALITIS 


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GENERAL  AND  HISTORICAL  CONSIDERATIONS    13 

surviving,  but  no  mention  is  made  whether  the  child  showed 
any  lethargic  symptoms.  Four  deaths  are  recorded.  It  is 
interesting  to  compare  the  low  mortality  in  these  patients 
with  the  extremely  high  mortality  of  influenza  in  pregnancy. 
The  question  of  the  influence  of  encephalitis  on  the  offspring 
is  of  even  greater  interest,  but  is  rather  difficult  to  answer 
at  present. 

Familial  Incidence.  In^only  five  instances,  a  little  over 
one-half  of  1  per  cent,  did  the  disease  occur  in  two  members 
of  one  family.  There  were  two  other  instances,  but  both  are 
doubtful  and  one  of  them  occurred  in  a  servant  of  the  house. 
Considering  the  rarity  of  the  instances  one  may  well  look 
upon  them  as  accidental;  and  in  view  of  the  practical  absence 
of  contagion  in  hospital  cases  (two  interns  did  contract  the 
disease),  one  may  consider  the  fact  of  direct  transmission  as 
almost  negligible. 

Clinical  Forms  and  Anatomical  Localizations.  The  great 
variety  of  clinical  forms  or  types  which  were  encountered, 
make  a  uniform  classification  very  difficult,  if  not  impossible. 
The  nomenclature  varied  with  many  observers,  which  added 
to  the  difficulty.  Some  divided,  subdivided  and  classified 
their  cases  by  creating  types  for  every  noticeable  departure 
from  the  general  picture,  while  others  grouped  them  all 
under  one  or  two  heads.  The  anatomical  substratum  fur- 
nished justification  for  the  former,  whereas  clinical  and 
etiological  considerations  guided  the  latter. 

The  following  questions  submitted  to  Dr.  Wechsler  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Barker:  I  would  like  to  ask  if  the  incidence  among  physi- 
cians could  be  due  to  the  fact  that  all  of  the  cases  were  recognized 
by  most  of  them.  They  would  know  where  to  go  to  get  a  diagnosis 
in  the  first  place,  whereas  large  numbers  of  the  general  population 
perhaps  don't  recognize  it.  Would  that  be  a  possible  explanation? 

Dr.  Wechsler:  I  do  not  know  if  that  would  be  a  warranted 
assumption.  Most  of  the  men  reported  on  all  the  cases.  It  is  a 
fact  that  struck  me  as  exceptional. 


i4  ACUTE  EPIDEMIC  ENCEPHALITIS 

Pathogenesis  (Leo  Loewe  and  Israel  Strauss).  Ber- 
kefeld  filtrates  of  brain  material,  nasopharyngeal  mucous 
membrane  and  nasal  washings  from  cases  of  epidemic 
encephalitis  have  produced  in  rabbits  and  monkeys  lesions 
typical  of  this  disease.  Spinal  fluid  and  blood  of  cases  have 
also  produced  the  disease  experimentally  in  these  animals. 
Many  of  these  animals  have  succumbed  with  the  typical 
picture  of  epidemic  encephalitis.  The  virus  has  been  passed 
through  many  series  of  animals.  It  can  be  preserved  for 
many  months  in  50  per  cent  glycerol. 

Cultures  made  on  ordinary  mediums  and  by  Rosenow's 
technique  have  proved  negative. 

By  means  of  the  ascitic-tissue  culture  methods  perfected 
by  Noguchi  a  minute,  filtrable  organism  from  cases  of 
epidemic  encephalitis  has  been  cultivated,  using  brain, 
nasopharyngeal  mucous  membrane,  nasopharyngeal  wash- 
ings, spinal  fluid  and  blood. 

This  same  organism  has  been  recovered  from  the  brain  and 
nasopharyngeal  mucous  membrane  of  animals  that  have  been 
inoculated  with  virus,  and  with  cultures  which  have  suc- 
cumbed to  the  experimental  disease.  The  cultures  recovered 
from  these  animals  have  produced  the  disease  when  injected 
into  other  animals  and  the  organism  has  again  been  isolated. 
Positive  animal  inoculations  have  been  obtained  with  the 
15th  generation  of  this  organism.  It  has  been  established 
that  the  organism  survives  contact  with  50  per  cent  glycerol 
for  several  days,  and,  providing  strict  anaerobic  conditions 
are  maintained,  remains  viable  in  individual  cultures  as  long 
as  twelve  months. 

Isolated  colonies  of  the  organism  in  the  solid  Noguchi 
medium  have  been  picked  and  successful  subinoculations 
secured  in  fluid  medium.  These  fluid  cultures  have  also 
produced  encephalitis  in  animals. 

Results  indicate  that  epidemic  encephalitis  can  be  dif- 
ferentiated from  epidemic  poliomyelitis  for  the  following 
reasons:  Rabbits  are  susceptible  to  infectious  material  from 
epidemic  encephalitis  and  not  from  poliomyelitis.  Monkeys 


GENERAL  AND  HISTORICAL  CONSIDERATIONS    15 

are  very  susceptible  to  poliomyelitis  and  relatively  refractory 
to  material  from  epidemic  encephalitis.  Spinal  fluid  from 
poliomyelitis  cases  is  innocuous  when  injected  into  rabbits 
and  monkeys,  whereas  spinal  fluid  from  cases  of  epidemic 
encephalitis  produces  typical  lesions  of  the  disease  in  both  of 
these  animals. 

Control  studies  have  been  uniformly  negative  with 
material  obtained  from  patients  suffering  from  or  dead  of 
conditions  other  than  epidemic  encephalitis. 

Further  work  done  by  Loewe  and  Strauss  since  their  last 
publication  in  the  Journal  of  Infectious  Diseases  (1920,  xxvii, 
250),  affords  them  additional  data  for  affirming  the  conclu- 
sions just  cited.  They  have  had  occasion  to  subject  to  animal 
inoculation  and  culture  additional  infectious  material,  such 
as  brain,  nasal  washings  and  cerebrospinal  fluid  from  en- 
cephalitis cases.  A  tabulation  reveals  that  their  experimental 
evidence  has  been  adduced  from  a  study  of  the  following 
human  material:  26  brains,  18  nasopharyngeal  mucous 
membranes,  29  nasopharyngeal  washings,  40  spinal  punc- 
tures, and  blood  from  4  cases.  In  the  course  of  their  experi- 
ments to  date  they  have  utilized  some  640  monkeys  and 
more  than  600  rabbits. 

Human  brain  from  cases  of  epidemic  encephalitis  is 
infectious  for  both  rabbits  and  monkeys,  decidedly  more  so 
for  rabbits.  Only  20  per  cent  of  monkeys  are  susceptible; 
on  the  other  hand,  at  most,  go  per  rent  of  rabbits  have  a 
natural  immunity.  It  has  been  possible,  by  repeated  trans- 
missions Tnrough  rabbits,  to  obtain  a  fixed  virus  which  is 
more  potent  for  monkeys.  It  has  been  found  likewise  that 
with  "fixing"  of  the  virus  a  definite  incubation  period  is 
established.  Filtration,  refiltration  and  glycerolation  all  tend 
to  increase  the  incubation  period.  Material  for  inoculation 
was  taken  usually  from  the  midbrain  where  the  most  pro- 
nounced lesions  of  this  disease  are  found.  Berkefeld  filtrates 
of  brain  from  9  cases  of  epidemic  encephalitis  were  injected 
intracranially  with  a  total  of  forty-seven  rabbits.  Of  these, 
twenty-four  succumbed  to  the  disease,  the  average  incuba- 


i6  ACUTE  EPIDEMIC  ENCEPHALITIS 

tion  period  being  ten  days.  The  virus  was  carried  in  series 
through  as  many  as  five  generations.  Encephalitis  was 
produced  in  nine  out  of  seventeen  rabbits  by  means  of 
emulsions  of  human  brain  from  3  cases,  the  average 
incubation  period  being  five  days.  Here  again  the  virus 
remained  virulent  through  as  many  as  five  animal  transmis- 
sions. Monkeys  succumbed  to  inoculation  of  infected  central 
nervous  tissue  in  six  instances.  The  clinical  manifestations  in 
many  instances  were  remarkably  like  those  found  in  the 
human.  (See  lethargic  states,  paralysis,  convulsions  and 
myoclonus.) 

Dr.  Harold  T.  Amoss  and  his  confreres  at  the  Rocke- 
feller Institute,  using  similar  material  to  that  used  by  Loewe 
and  Strauss,  described  above,  have  been  unable  up  to  the 
present  time  when  the  meeting  was  held  (December,  1920) 
to  verify  the  findings  of  the  latter.  For  a  description  of  their 
work  the  reader  is  referred  to  the  chapter  on  laboratory 
experimentation. 

Confirmation  of  Findings  of  Loewe  and  Strauss 
(William  M.  Thalhimer).  The  epidemic  encephalitis 
material  on  which  my  investigation  and  report  are 
based  consist  of  two  spinal  fluids  and  four  autopsies. 
Mandler  filters,  tested  to  hold  back  bacillus  prodigiosus, 
were  used  in  preparing  filtrates  from  the  central  nervous 
system.  Rabbits  were  injected  intracranially  by  the  method 
of  Loewe.  Guinea-pigs  were  also  injected  by  a  similar  method. 
Cultures  were  made  on  ascitic  fluid  tissue  medium,  as  per- 
fected by  Noguchi.  The  brains  of  the  rabbits  and  guinea-pigs 
which  succumbed  to  the  infection  were  removed  with  aseptic 
precautions.  About  50  per  cent  of  the  rabbits  succumbed 
after  inoculation.  They  died  on  the  average  of  from  ten 
days  to  three  or  four  weeks.  Some  of  them  apparently  died 
rather  suddenly  and  were  found  dead  in  their  cages,  after 
having  been  apparently  well  the  day  before.  Various  types 
of  palsy  appeared  in  some  of  the  rabbits,  corresponding  to 
different  types  in  human  cases,  such  as  peripheral  palsy, 


GENERAL  AND  HISTORICAL  CONSIDERATIONS    17 

difficulty  in  swallowing,  inability  to  swallow,  typical  myoc- 
lonus, etc.  Palsy  and  apparent  illness  did  not  appear  in 
guinea-pigs,  the  animals  being  found  dead  in  their  cages 
after  having  been  apparently  well. 

The  central  nervous  system  of  the  rabbits  and  guinea-pigs 
showed  typical  lesions  of  epidemic  (lethargic)  encephalitis. 
These  were  not  always  the  same  and  there  was  not  always 
present  the  well-marked  perivascular  round  cell  infiltration. 
In  some  animals  only  minute  hemorrhages  were  present. 
In  the  cultures  of  ascitic  fluid  tissue  media  a  minute,  filtrable 
organism,  identical  in  all  respects  with  that  described 
by  Loewe  and  Strauss,  was  cultivated  from  the  original 
material  and  from  material  secured  from  the  animals. 
Cultures  of  this  organism  were  injected  into  rabbits  and  also 
into  guinea-pigs  and  produced  the  disease  with  typical 
lesions.  These  animals  did  not  die  as  quickly  as  those  inocu- 
lated with  the  virus,  as  they  usually  lived  from  eight  to 
twelve  weeks  after  inoculation.  The  organism  was  again 
recovered  from  these  animals. 

This  organism  has  been  carried  through  many  generations. 
Some  of  the  strains  are  at  present  in  the  12th  generation. 

Control  cultural  studies  were  made  of  the  medium  used 
and  of  all  the  types  of  the  material  cultured,  with  negative 
results.  Control  animals  were  inoculated  with  materials 
similar  to  the  various  types  used  in  the  experiments.  These 
animals  continued  well.  Some  of  them  were  sacrificed  and 
showed  no  lesions  in  their  central  nervous  system. 

The  results  of  this  investigation  are  confirmation  of  both 
the  experimental  and  the  cultural  studies  of  Loewe  and 
Strauss. 

The  following  questions  submitted  to  Dr.  Thalhimer  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Sachs:  I  would  like  to  ask  Dr.  Thalhimer  if  his  methods 
were  essentially  the  same  as  were  pursued  at  the  Mt.  Sinai 
Laboratory? 


18  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Thalhimer:  They  were  essentially  the  same.  I  think  they 
were  quite  identical. 

Dr.  Skoog:  Has  Dr.  Thalhimer  had  any  training  with  Noguchi 
in  the  Rockefeller  Institute  prior  to  his  work  in  this  subject? 

Dr.  Thalhimer:  No.  I  had  no  training  with  Dr.  Noguchi 
whatsoever.  On  several  visits,  however,  to  New  York,  I  was  with 
Dr.  Loewe  and  Dr.  Strauss  at  their  laboratory,  and  they  were 
kind  enough  to  show  me  their  work  and  their  methods  very 
thoroughly,  and  I  was  in  communication  with  them  quite  con- 
stantly during  the  work,  and  can  say  that  I  learned  a  great 
deal  from  them  as  to  how  to  conduct  this  work  culturally  and 
experimentally  in  animals,  etc.,  and  I  also  had  the  privilege  and 
pleasure  of  having  Dr.  Loewe  out  in  my  laboratory  for  almost 
two  weeks  last  summer,  where  I  was  able  to  show  him  my  work 
and  able  also  to  give  him  some  of  my  material  which  he  brought 
back  with  him  and  I  think  also  worked  with. 

Dr.  Sachs:  May  I  ask  whether  the  methods  of  the  French 
authors,  of  Levaditi,  etc.,  are  identical  with  the  methods  that 
have  been  employed  by  these  three  gentlemen  in  this  group? 

Dr.  Thalhimer:  There  has  been  no  publication  by  any  of  these 
other  investigators  as  to  the  successful  cultivation  of  a  filtrable 
organism,  and  there  has  been  no  mention  in  the  literature  that  I 
have  seen  that  they  have  been  using  the  tissue  ascitic  fluid  culture 
method  perfected  by  Noguchi.  Whether  that  work  is  under  way 
there  or  not  one  cannot  judge  from  literature.  So  far  as  one  can 
make  out  the  nature  of  the  filtrates  which  they  have  prepared, — 
and  if  I  am  wrong  I  hope  you  will  correct  me, — the  nature  of  the 
filtrates  that  have  been  used,  is  very  similar,  and  the  injection  of 
emulsions  and  things  of  that  sort  are  of  course  simple  methods  and 
are  necessarily  identical.  An  important  phase  of  the  work  is 
whether  this  is  a  filtrable  virus  and  a  filtrable  organism;  and  there 
not  having  been  published  any  work  whatsoever  on  an  organism 
it  would  leave  that  question  unsolved.  But  the  filtrates  which 
they  have  used  would  confirm  the  work  that  has  been  done  by 
Loewe  and  Strauss  as  far  as  the  disease  being  caused  by  virus 
which  will  pass  through  a  clay  filter  that  will  hold  back  ordinary 
organisms. 

Dr.  Loewe:  They  state  definitely  that  virus  experiments 
have  been  formed  with  definite  filtrates,  and  in  this  case  they  use 
both  Berkefeld's  and  Chamberland's  filters.  They  make  no 
mention  at  all  of  employing  the  Noguchi  medium. 


GENERAL  AND  HISTORICAL  CONSIDERATIONS    19 

Dr.  Skoog:  Is  every  filtrable  virus  anaerobic? 

Dr.  Thalhimer:  I  don't  think  that  I  can  answer  that.  That 
would  mean — Can  one  cultivate  from  a  filtrable  virus  an  organism 
only  by  anaerobic  methods?  Dr.  Loewe  seems  to  think  he  can 
answer  that  question. 

Dr.  Loewe:  The  cultural  work  done  by  Noguchi  on  his  organism 
reveals  the  fact  that  after  the  organism  has  become  saprophytized 
it  is  possible  to  grow  the  organism  in  the  presence  of  oxygen,  and 
Noguchi  in  his  yellow  fever  work  which  also  described  the  filtrable 
virus,  filtrable  organism,  grows  it  in  a  medium  and  shows  that 
certain  strains  will  grow  nearer  the  surface  of  the  medium,  indi- 
cating a  necessity  for  a  certain  amount  of  oxygen  being  present. 

Dr.  Strauss:  Dr.  Loewe  has  forgotten  to  state  that  we  have 
attempted  to  grow  this  organism  aerobically  and  we  have  failed. 
The  question  was:  Is  the  virus  necessarily  anaerobic?  A  virus 
isn't  anaerobic.  A  virus  lives  in  any  atmosphere.  That  is  the 
answer.  The  organism  that  we  have  obtained  from  the  virus  is 
anaerobic,  and  until  now  we  have  not  succeeded  in  growing  it 
aerobically. 

CONCLUSIONS    OF   THE    COMMISSION 

The  Commission  is  of  the  opinion  that  final  conclusions 
as  to  etiology,  pathogenesis  and  incidence  are  not  warranted 
at  this  stage  of  our  knowledge  of  lethargic  encepKalitis.  The 
general  historical  consideration  of  the  disease,  as  discussed 
by  Dr.  Lewellys  F.  Barker,  indicates  the  extent  and  the 
limits  of  our  knowledge  of  lethargic  encephalitis.  The  data 
furnished  by  Dr.  Shirley  W.  Wynne  indicate  the  extent, 
characteristics  and  mortality  of  the  disease,  not  only  in  the 
neighborhood  of  New  York,  but  in  other  localities;  and  the 
statistical  material  collected  by  Dr.  Wechsler  forms  a 
particularly  valuable  contribution  to  the  history  of  the 
disease  in  this  country  up  to  the  time  of  his  report.  Comment 
is  reserved  on  the  observations  of  Drs.  Leo  Loewe  and 
Israel  Strauss  and  likewise  upon  Dr.  William  M.  Thal- 
himer's  report  in  Chapter  VII. 

It  is  well  understood  that  at  this  stage  of  our  knowledge 
the  life  history  of  the  disease  is  not  fully  known.  We  know  it 


20  ACUTE  EPIDEMIC  ENCEPHALITIS 

as  yet  chiefly  in  cross  section.  The  characteristics  of  the 
causative  organism  are  not  fully  established;  the  mode  of 
conveyance  cannot,  therefore,  be  determined.  Neither  is  the 
clinical  course  entirely  appreciated  in  all  respects.  Further 
knowledge  of  the  disease  from  all  these  standpoints  is  neces- 
sary before  a  final  description  and  definition  of  it  is  war- 
ranted. It  is  one  of  those  conditions,  like  syphilis,  of  which  a 
life  history  is  necessary  before  it  is  fully  understood. 


Chapter  II 

SYMPTOMATOLOGY:  SYMPTOMS  REFERABLE  TO 

THE  BRAIN 

THIS  chapter  deals  with  the  symptomatology  of  epidemic 
encephalitis  referable  to  the  brain.  The  general  features 
of  symptomatology  are  discussed  by  Dr.  Lewellys  F.  Barker 
of  Baltimore;  the  modes  of  invasion  of  the  disease  are  dis- 
cussed by  Dr.  Isador  Abrahamson  of  New  York  City;  the 
cerebral  types  by  Dr.  John  W.  McConnell  of  Philadelphia; 
the  striatal  of  thalamic  symptoms  by  Dr.  J.  Ramsay  Hunt  of 
New  York;  the  auditory  and  vestibular  disorders  by  Dr. 
Isidore  Friesner  of  New  York;  symptoms  referable  to  the 
eye  by  Dr.  Ward  A.  Holden  of  New  York;  and  cerebellar 
symptoms  by  Dr.  J.  P.  Crozer  Griffith  of  Philadelphia. 

Modes  of  Onset  (Lewellys  F.  Barker).  The  initial 
symptoms  of  epidemic  encephalitis  have  varied  much  in 
different  epidemics.  Thus,  in  the  first  Vienna  epidemic,  there 
was  usually  a  fore-stage  with  symptoms  of  slight  meningeal 
irritation,  which  was  soon  followed  by  somnolence  and  by 
ophthalmoplegia.  In  the  191 8  epidemic  in  Australia,  there 
was  an  initial  stage  of  excitation  (with  headache  and,  some- 
times, convulsions),  and  only  several  days  later  did  the 
somnolence,  the  fever  and  the  signs  of  paralysis  appear. 
In  the  cases  first  observed  by  Netter  in  France  (19 18)  symp- 
toms of  meningeal  irritation  were  absent,  but  fever  was  more 
common  than  in  the  Viennese  experience;  the  symptomatic 
triad  described  by  Netter  consisted  of  fever,  somnolence  and 
ophthalmoplegia  externa.  English  observers  (19 18)  recorded 
asthenia,  malaise,  headache,  general  pains,  chills,  nausea, 
anorexia  and  catarrhal  inflammations  of  the  respiratory 
tract  as  symptoms  of  the  initial  stage,  to  be  followed  in  a 


21 


22  ACUTE  EPIDEMIC  ENCEPHALITIS 

few  days,  or  sometimes  almost  at  once,  with  any  one  of 
several  clinical  pictures  (somnolence  with  ophthalmoplegia; 
bulbar  paralysis;  catatonic  stupor;  or,  comparatively  fre- 
quently, a  Parkinson-like  syndrome).  In  the  United  States, 
initial  stages  of  various  sorts  have  been  described.  When  the 
onset  was  sudden,  there  was  often  severe  pain  in  the  head, 
fever,  and  delirium,  followed  by  a  period  of  improvement  for 
a  few  days,  after  which  apathy,  somnolence  and  cerebral 
nerve  paralyses  of  different  sorts  or  Parkinson-like  syn- 
dromes developed.  When  the  onset  was  more  insidious,  the 
initial  symptoms  often  consisted  of  diplopia  and  slight 
mental  confusion,  or,  in  some  cases,  of  neuralgias  or  of 
pareses  in  the  domain  of  one  or  more  of  the  cerebral  nerves; 
and  these  patients,  too,  often  showed  improvement  for 
a  few  days  only  to  become  somnolent  later.  Not  infre- 
quently there  was  marked  restlessness  at  night  with  insomnia 
before  a  stage  of  somnolence  was  reached.  In  the  Hamburg 
epidemic  of  19 18-19  described  by  Nonne,  such  an  initial  stage 
as  above  described  does  not  seem  to  have  been  marked,  the 
disease  frequently  having  been  ushered  in  by  paralyses  in  the 
domain  of  the  cerebral  nerves  or  by  a  Parkinson-like  syn- 
drome. In  the  recent  epidemic  in  Italy,  Switzerland,  Austria 
and  parts  of  Bohemia  (19 19-1920)  the  prodromal  phenomena 
have  consisted  of  anorexia,  headache,  vague  rheumatic  pains, 
sometimes  diplopia,  and  slight  fever  lasting  for  three  or  four 
days.  Then  somnolence  and  external  ophthalmoplegia 
followed  as  in  other  epidemics,  but  in  addition,  certain 
hyperkinetic  phenomena  (myoclonia,  choreatic  disturbances 
of  motility,  etc.)  have  been  very  common.  During  1920, 
hyperkinetic  cases  have  been  occurring  also  in  America. 
It  would  seem  probable,  now,  that  some  of  the  cases  de- 
scribed in  France  as  early  as  191 7  as  "Cruchet's  disease" 
were  instances  of  the  hyperkinetic  form  of  epidemic  enceph- 
alitis. 

Prodromata  and  Invasion  (Isador  Abrahamson).     Le- 
thargic  encephalitis   has   the   prodromata   common   to   all 


SYMPTOMATOLOGY  23 

general  infections.  There  are  in  addition  certain  special 
characteristics.  Thus  a  catarrhal  inflammation  accompanied 
by  fever  of  a  certain  degree  and  course,  and  by  certain 
changes  in  the  contents  of  the  blood  and  cerebrospinal  fluid, 
may  raise  the  possibility  of  lethargic  encephalitis;  con- 
comitant eye  symptoms  may  increase  that  possibility  to  a 
probability;  and  the  mental  picture  may  make  that  prob- 
ability a  certainty.  The  nasopharyngeal  area  of  the  res- 
piratory tract  is  the  mucous  membrane  usually  infected,  but 
in  one  case  or  another,  almost  every  mucous  membrane  in  the 
body  may  be  affected.  The  lining  of  the  auditory  passages 
seldom  escapes;  and  the  nasal  and  accessory  sinuses  are  very 
often  attacked  too.  Sometimes  the  bronchial  mucosa,  some- 
times the  intestinal  is  the  main  seat  of  invasion.  And  the 
localization  or  spread  of  the  catarrhal  inflammation  may 
further  serve  to  multiply  differences  between  individual 
cases.  But  whether  a  rhinitis,  or  a  sinusitis,  or  otitis,  or  an 
enteritis,  or  a  pneumonia  dominantly  confronts  us,  the 
morbid  process  is  fundamentally  the  same. 

From  the  initial  site  of  attack  the  toxin  is  diffused  through- 
out the  body,  but  the  organisms  tend  to  spread  chiefly 
along  the  lymphatics  of  the  nerve  trunks.  Hence,  to  local 
catarrhal  inflammation  and  general  toxemia,  are  added  signs 
of  implication  of  the  nerve  structures  in  anatomical  connec- 
tion with  the  first  infected  mucous  sites.  In  the  middle  ear 
involvements,  otic  ganglion  pain  and  seventh  nerve  weak- 
ness appear;  in  sinus  involvement,  the  fifth  nerve;  in  naso- 
pharyngeal involvement,  the  medullary  and  upper  spinal 
nuclei;  in  gastro-intestinal  involvement  the  dorsolumbar 
cord.  While,  as  a  rule,  the  attack,  having  become  evident, 
reaches  its  height  and  then  progressively  declines  within  a 
period  of  ten  to  twenty  days,  sometimes  it  lasts  longer,  and 
sometimes  it  is  intermittent  and  sometimes  it  recurs.  In  such 
cases,  we  are  dealing  either  with  reinfections  or  with  multiple 
infections  or  with  a  wavering  resistance. 

It  is  noteworthy  that  the  main  stress  of  this  infection 
falls  upon  the  most  highly  organized  cells,  the  nerve  cells. 


24  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  more  highly  organized  a  cell  is,  the  more  vulnerable  it  is. 
When  all  cells  are  exposed  to  the  same  toxic  agent,  the  more 
vulnerable  suffer  most;  and  the  rest  suffer  in  the  order  of 
their  vulnerability.  And  among  the  nerve  cells  certain  cells 
are  more  delicate  than  others.  Hence,  the  function  of  thought 
almost  invariably  is  deranged  in  lethargic  encephalitis.  We 
see  somnolent,  maniacal,  depressive  and  other  psychotic 
cases.  Again,  we  should  emphasize  the  necessity  of  consider- 
ing such  cases  not  as  types  of  disease  but  as  types  of  reaction; 
not  so  much  from  the  point  of  view  of  the  organism  as  from 
the  point  of  view  of  the  individual.  The  functional  derange- 
ment is  excited  by  the  infection,  but  the  form  and  the  degree 
of  the  derangement  are  determined,  at  least  in  part,  by  the 
circumstances  which  determined  the  mental  constitution  of 
the  case.  The  infection  evokes  not  a  special  type  of  the  disease 
but  makes  manifest  a  latent  weakness  in  the  mental  make-up, 
and  this  weakness  may  persist  after  all  other  evidence  of  the 
infection  has  passed  away. 

The  following  questions  submitted  to  Dr.  Abrahamson 
before  the  Commission,  together  with  the  answers  to  them, 
are  here  reported  verbatim: 

Dr.  Dana  :  Do  you  think  it  is  well  established  and  agreed  upon 
by  all  observers  that  the  disease  always  begins  by  attacking  certain 
mucous  membranes,  so  that  these  can  be  observed  to  be  attacked 
and  to  be  diseased? 

Dr.  Abrahamson:  A  careful  study  of  the  histories  which  has 
been  neglected  by  the  other  observers — they  have  gone  right  to  the 
lethargic  encephalitis  and  neglected  the  original  point — will 
elicit  that  practically  every  on&  has  started  with  some  catarrh  of 
one  of  the  mucous  membranes/If  you  read  the  histories  in  litera- 
ture, they  mention  this,  but  pass  it  by  and  regard  it  as  a  symptom 
of  fever.  I  have  seen  it  begin  originally  with  conjunctivitis  of  one 
eye,  followed  by  a  fearful  pain  in  the  face,  and  then  a  neuropara- 
lytic ophthalmia  of  that  one  eye. 

Dr.  Dana:  You  have  stated  that  the  more  highly  organized 
the  nerve  cell  the  more  vulnerable  it  is  to  attack.  Do  you  not  con- 


SYMPTOMATOLOGY  2$ 

sider  the  motor  nuclei  of  the  third  nerve  as  more  highly  organized 
than  those  of  the  rolandic  area? 

Dr.  Abrahamson:  There  are  certain  accidental  conditions  in 
the  disease.  In  the  first  place,  I  am  speaking  of  the  general  effects  of 
the  toxemia  of  lethargic  encephalitis,  causing  the  general  symp- 
toms, such  as  lethargy  and  changes  in  the  mental  states  which 
occur  at  the  same  time.  It  is  an  accident,  owing  to  the  nasal  locali- 
zation, that  the  oculomotor  nuclei  are  involved.  That  is  an  accident 
of  the  spread  of  the  infection  from  the  nose  and  throat  to  the  pons, 
which  I  thought  I  brought  out  in  the  paper,  but  the  general  effect 
of  the  toxemia  of  the  disease  causes  the  nuclei  to  be  lethargic,  and 
causes  typical  mental  symptoms  which  I  believe  are  characteristic 
and  present  in  every  case. 

Dr.  Dana:  In  other  words,  if  you  had  the  poison  or  toxemia  of 
this  disease  and  could  inject  it  into  a  man  or  an  animal,  do  you 
think  it  would  affect  his  physical  functions  first  and  the  more 
highly  organized  cells  of  the  cortex,  and  would  not  affect  the 
midbrain? 

Dr.  Abrahamson:  I  believe  that  if  you  inject  the  toxin  intra- 
peritoneally,  the  oculomotor  nuclei  would  not  be  especially 
involved.  This  is  not  established;  it  is  my  opinion  only. 

Dr.  Dana:  In  the  experiment  on  animals,  does  it  work  that 
way? 

Dr.  Abrahamson:  The  toxin  has  been  injected  intraperitoneally 
and  the  spinal  cord  has  been  involved  along  with  a  more  general 
involvement,  but  it  is  difficult  in  animals  to  differentiate  as  to 
mental  changes.  All  humans  show  mental  changes. 

Dr.  Dana:  In  describing  or  classifying  this  disease,  would 
you  not,  after  all — apart  from  any  question  of  accident  on  account 
of  the  nasopharynx  being  near  the  midbrain — say  that  practically 
all  of  the  disease  groups  itself  around  the  midbrain  syndrome? 
After  all,  you  look  for  symptoms  due  to  some  trouble  with  the 
midbrain  and  motor  nerves  of  the  eye,  and  particularly  the  motor 
functions,  as  being  the  dominant  thing  right  through. 

Dr.  Abrahamson:  The  dominant  point  of  entrance  after  all 
happens  to  be  the  nasal  pharynx.  You  have  to  postulate  away  the 
point  of  entrance,  and  I  think  it  is  definitely  proven  that  the 
infection  passes  through  the  nerve  sheaths.  Those  of  you  who  are 
familiar  with  the  work  of  Orr  and  Rows  may  remember  that  by 


26  ACUTE  EPIDEMIC  ENCEPHALITIS 

placing  capsules  of  bacteria  at  various  levels  they  got  infections 
corresponding  to  the  level  at  which  they  placed  the  capsule,  and 
the  nearer  the  point  was  to  the  capsule  the  more  diseased  it  was, 
and  the  further  away  it  spread  from  the  capsule  of  germs  the  less 
the  disease  was.  It  is  a  fact  that  the  majority  of  cases  begin  in  the 
nasopharynx.  There  are  spinal  types,  too.  I  have  seen  three 
definite  spinal  types. 

Dr.  Dana  :  I  would  like  to  ask  you  if  you  get  many  symptoms 
involving  the  functions  of  the  olfactory  nerve? 

Dr.  Abrahamson  :  That  is  a  very  difficult  thing  to  test  in  these 
individuals.  In  the  first  place,  we  have  not  laid  much  stress  on  it 
because  so  many  have  rhinitis  and  pharyngitis  that  it  is  very 
difficult  to  test  the  olfactory  function.  Again,  during  the  lethargic 
stage,  it  is  very  difficult  to  test  these  individuals  so  far  as  the 
olfactory  function  is  concerned.  The  olfactory  function  varies  so 
much  that  one  can  hardly  lay  much  stress  on  it. 

Dr.  Taylor:  From  a  practical  standpoint  would  you  overthrow 
all  the  classifications  which  you  allude  to  in  the  beginning, — all 
the  types?  I  am  speaking  purely  from  a  practical  standpoint. 

Dr.  Abrahamson:  Dr.  Wechsler  who  will  speak  upon  types, 
has  collected  about  38  types,  I  believe.  I  think  they  create  con- 
fusion, and  especially  when  we  regard  the  chronic  cases.  When 
you  see  the  chronic  cases  and  you  see  the  mental  cases  and  find 
that  the  make-up  of  the  individual  is  responsible  for  most  of  the 
mental  reactions  in  the  mental  cases,  just  as  is  the  case  in  influenza, 
— that  is  the  reason  I  accentuate  the  make-up  of  the  individual  and 
the  type  of  resistance  rather  than  the  localization. 

Dr.  Taylor:  That  is  the  theoretical.  What  I  asked  was  whether 
we  should  stop  at  theorizations  and  not  carry  them  out  to  the 
practical. 

Dr.  Abrahamson  :  No,  I  would  not  absolutely  throw  them  over, 
but  I  think,  rather  than  anatomically,  I  would  go  according  to 
the  severity  of  the  disease  in  the  way  one  does  ordinarily  in 
infectious  diseases. 

Dr.  Taylor:  You  say  "the  severity  of  the  disease."  Would 
you  call  the  paralysis  agitans,  type  A,  more  severe  than  the 
psychotic  type? 

Dr.  Abrahamson:  No. 

Dr.  Taylor:  That  is  a  vague  idea,  it  seems  to  me. 


SYMPTOMATOLOGY  27 

Dr.  Patrick:  I  would  like  to  inquire  whether  you  have  any 
definite  evidence  that  in  this  disease  the  virus  travels  from  the 
nasopharynx  along  the  nerve  trunks  to  the  midbrain? 

Dr.  Abrahamson:  There  is  nothing  definite.  I  am  giving  you  a 
clinical  view,  not  a  pathological  view. 

Cerebral  Types  (John  W.  McConnell).  This  term 
should  be  applied  only  to  those  cases  that  exhibit  a  sympto- 
matology in  consonance  with  the  known  anatomy  and 
physiology  of  the  cerebrum.  This  would  include  such  symp- 
toms as  headache,  vertigo,  delirium;  hebetude;  euphoria;  an 
unusual  tendency  to  facetiousness;  liability  to  automatism 
and  to  the  automatic  reproduction  of  familiar  movements  in 
purposeless  fashion;  speech  disturbances  and  amnesias,  the 
latter  however  most  commonly  seen  in  cases  presenting 
marked  hebetude;  convulsions,  both  general  and  Jacksonian; 
monoplegias;  hemiplegias  with  increased  deep  reflexes,  Bab- 
mski's  sign  and  persistent  ankle  clonus.  Lethargy,  somnolence 
and  insomnia  are  symptoms  mentioned  in  order  of  the 
frequency  of  their  occurrence,  the  lethargy  being  less 
marked  than  the  clinical  signs  pertaining  to  the  motor 
system.  Occasionally,  the  fulminating  character  of  the 
symptoms  suggested  a  cerebral  apoplectic  form  of  epidemic 
encephalitis. 

In  the  cases  observed  there  was  little  deviation  from  the 
symptomatology  of  recorded  cases.  The  aphasia  was  of  the 
so-called  motor  type.  Perception  was  intact,  but  the  ability 
to  use  articulate  language  was  gone.  The  paralytic  phenomena 
were  associated  with  increased  reflexes,  Babinski's  sign  and 
persistent  ankle  clonus.  Lethargy  was  noticeable  and  could 
probably  be  better  termed  apathy.  Insomnia  was  found  in  one 
case  in  the  height  of  the  disease;  in  one  or  two  others  in  the 
convalescent  stage.  The  absence  of  sensory  features,  or  rather 
fne  emphasis  of  motor  features  was  a  striking  observation 
in  all  cases. 

The  accompanying  clinical  histories  give  a  picture  of  the 
so-called  cerebral  type. 


7U   OJUA 

28  ACUTE  EPIDEMIC  ENCEPHALITIS 


Case  I.  A  man,  aged  sixty-two,  clerk  by  occupation,  was  admit- 
ted to  the  University  Hospital  early  in  1920,  having  been  ill  for 
about  two  weeks  with  headache,  vomiting,  fever,  and  general 
prostration  associated  with  double  vision.  On  admission  he  was 
somnolent,  confused,  disoriented,  and  showed  some  weakness  of 
ocular  muscles,  together  with  slight  weakness  ot  the  right  face. 
There  was  no  weakness  of  the  extremities.  The  tendon  reflexes 
were  normal.  During  his  stay  in  the  hospital  he  gradually  developed 
a  right  hemiplegia,  with  inability  to  speak  distinctly.The  tendon 
reflexes  were  increased  on  the  right  side;  ankle  clonus  was  obtained 
as  well  as  the  Babinski  sign.  He  became  addicted  to  facetious 
remarks,  most  of  which  were  without  foundation  or  relation  to 
conversation.  He  was  delusional,  and  expressed  ideas  of  great 
wealth.  The  hemiplegic  state  lasted  about  one  week  and  cleared 
up  without  any  vestige  remaining.  His  improvement  was  gradual 
but  steady.  During  convalescence  there  was  insomnia,  headache, 
inability  to  concentrate,  and  weakness  of  the  lower  extremities 
At  the  present  time  he  is  apparently  well,  all  of  his  major  and 
minor  symptoms  having  disappeared. 

Case  II.  A  woman,  aged  seventy-one,  suffered  a  mild  attack 
of  influenza  in  19 18,  from  which  she  wholly  recovered.  For  four 
weeks  previous  to  my  seeing  her  she  complained  of  general  head- 
ache, feverishness,  physical  weakness  and  verbal  amnesia.  She  was 
more  somnolent  than  usual.  In  this  lethargic  state  she  presented  the 
appearance  of  bilateral  ptosis,  but  could  elevate  the  upper  lids 
by  putting  all  her  energy  into  the  act.  Gradually  she  lost  strength 
and  was  forced  to  go  to  bed,  having  developed  a  complete  inability 
to  speak  and  a  weakness  of  the  right  face,  right  arm  and  right 
leg.  At  this  time  she  was  apathetic,  somnolent  and  was  aroused 
with  difficulty.  Efforts  to  get  answers  to  questions  were  fruitless 
because  of  her  aphasia.  She  seemed  unable  to  cerebrate  sufficiently 
to  pantomine.  She  had  no  demonstrable  disturbance  of  the  cranial 
nerves.  The  eyegrounds  were  not  pathological.  She  was  not  deaf 
and  she  could  see.  No  disturbances  in  the  fields  of  vision  were 
demonstrable.  She  had  a  right-sided  hemiparesis  with  increased 
reflexes,  Babinski's  sign  and  ankle  clonus.  The  left  side  was  not 
involved.  She  had  no  incontinence  of  urine  or  feces.  There  was  no 
demonstrable  sensory  defect.  There  was  no  stiffness  of  the  neck 
or  of  the  spine,  and  Kernig's  sign  was  absent,  no  tache  cerebrale. 
The  diagnosis  of  epidemic  encephalitis  was  made.  She  became 


SYMPTOMATOLOGY  29 

more  stuporous,  less  responsive  to  external  stimuli,  and  without 
any  change  in  her  motor  condition  died  from  exhaustion  two  weeks 
later.  Necropsy  was  not  allowed. 

The  following  questions  submitted  to  Dr.  McConnell 
before  the  commission,  together  with  the  answers  to  them, 
are  here  reported  verbatim. 

Dr.  Dana:  Is  there  not  a  better  word  than  "cerebral"  type  to 
indicate  the  group  of  cases  that  you  are  referring  to?  What  is  a 
cerebral  type  from  your  point  of  view? 

Dr.  McConnell:  My  point  of  view  of  the  "cerebral"  type  is 
the  same  as  yours;  but  I  took  it,  the  way  the  title  was  given  to  me, 
that  I  was  to  devote  my  attention  to  the  portion  of  the  brain 
exclusive  of  the  basal  ganglia  and  medulla  oblongata,  etc. 

Dr.  Dana:  I  was  wondering  whether  the  term  "pallidal" 
type  would  not  be  better  than  "cerebral." 

Dr.  McConnell:  I  should  think  so. 

Dr.  Taylor:  The  adjective  "cerebral"  belongs  to  the  forebrain 
and  the  midbrain. 

Basal  Ganglia  Group:  Striatal  and  Thalamic  Types 
(J.  Ramsay  Hunt).  Of  clinical  manifestations,  those  related 
to  the  corpora  striata  have  aroused,  perhaps,  the  greatest 
interest.  This  is  partly  due  to  the  recent  advances  in  our 
knowledge  of  the  function  of  these  structures,  but  also  to 
the  extreme  rarity  of  this  localization  in  other  types  of 
inflammatory  disease.  No  other  acute  affection  of  the  central 
nervous  system  has  yielded  so  many,  and  such  striking 
evidences  of  involvement  of  the  great  basal  ganglia  as 
encephalitis  Iethargica. 

While  the  optic  thalamus  is  frequently  involved  in  encepha- 
litis, the  thalamic  symptoms  are  milder  and  less  serious 
than  are  those  of  the  striatum,  and  the  chief  emphasis  of 
this  study  will  be  placed  upon  the  latter. 

Anatomical  Considerations.  The  corpus  striatum  is  a 
large  ganglionic  structure  which  is  divided  by  the  anterior 


3o  ACUTE  EPIDEMIC  ENCEPHALITIS 

limb  of  the  internal  capsule  into  two  parts,  the  nucleus 
Ienticularis  and  the  nucleus  caudatus.  The  nucleus  Ienticu- 
Iaris  is  still  further  subdivided  into  an  external  segment, 
the  putamen,  and  an  internal,  which  is  termed  the  globus 


»•  *     .        .  it- 


J 
J 


<■*>%  ■ 


Fig.  2.  Juvenile  paralysis  agitans  of  twenty-five  years  duration.  Section 
through  the  putamen.  Note  the  increase  of  the  glia  nuclei  and  almost  com- 
plete absence  of  the  large  pallidal  cells.  The  small  ganglion  cells  are  not 
reduced  in  number. 

pallidus.  These  anatomical  divisions  are  based  upon  the  gross 
appearance  of  the  ganglion  and  are  purely  topographical. 

The  putamen  and  caudate  nucleus  are  identical  in  histo- 
logical structure  and  constitute  the  neostriatum. 

The  globus  pallidus  is  composed  of  two  segments,  an 
inner  and  an  outer.  This  portion  of  the  striatum  is  older 
phylogenetically  and  is  termed  the  paleostriatum. 


SYMPTOMATOLOGY  31 

A  much  greater  importance  is  to  be  attached  to  the  cellu- 
lar types  of  this  region  than  to  the  gross  anatomical  appear- 
ance and  subdivisions. 

The   paleostriatum    (pallidum)    contains   aggregations   of 


..jk'-X.'.s-'j*. 


Fig.  3.  Juvenile  paralysis  agitans.  Section  through  the  globus  pallidus, 
showing  atrophy  and  diminution  in  the  number  of  the  motor  cells.  Note  the 
increase  of  glia  nuclei  and  irregularly  formed  concrements. 


large  multipolar  cells,  which  are  histologically  of  the  motor 
type  (paleostriatal  or  pallidal  cells). 

The  neostriatum  (caudate  and  putamen)  is  composed  of 
two  cell  types.  Of  these,  the  more  numerous  are  small, 
polygonal  cells  which  give  the  characteristic  histological 
picture  of  this  region  (neostriatal  cells).  Scattered  among 
these  cells,  are  cells  of  much  larger  size.  These  are  giant 


32  ACUTE  EPIDEMIC  ENCEPHALITIS 

multipolar  cells,  containing  NissI  granules  and  deposits 
of  yellow  pigment,  and  are  of  the  same  type  as  the 
motor  cells  of  the  pallidum  (giant  pallidal  cells  of  the 
neostriatum). 

The  motor  or  pallidal  type  of  cells  is  present,  therefore, 
in  both  paleostriatum  and  neostriatum;  while  the  small 
neostriatal  cells  are  peculiar  to  the  neostriatum. 

In  19 1 7  I  was  able  to  demonstrate  in  juvenile  paralysis 
agitans,  widespread  atrophy  and  loss  of  the  large  pallidal 
cells  of  the  corpus  striatum,  and  referred  this  disorder  to  a 
primary  atrophy  of  this  motor  projection  system  of  the 
corpus  striatum  (primary  atrophy  of  the  pallidal  system). 
The  peculiar  and  characteristic  feature  of  this  lesion  was  its 
limitation  to  a  special  system  of  motor  neurons. 

When  the  pallidal  system  is  diseased  there  is  produced 
the  motor  syndrome  which  we  associate  with  paralysis 
agitans.  This  is  characterized  by  paralysis  of  automatic 
associated  movements,  muscular  rigidity  and  rhythmical 
tremor. 

The  writer  also  pointed  out  that  the  small  ganglion  cells  of 
the  neostriatum  which  were  well  preserved  in  juvenile 
paralysis  agitans,  showed  extensive  degeneration  and  atrophy 
in  Huntington's  chorea.  The  small  neostriatal  cells  were, 
therefore,  regarded  as  coordinating  and  inhibitory  in  func- 
tion. Because  of  this  elective  atrophy  of  special  systems  of 
cells  the  syndrome  chorea  was  referred  to  a  loss  of  the  strio- 
pallidal  or  neostriatal  system,  and  the  syndrome  paralysis 
agitans  was  referred  to  a  loss  of  the  pallidal  or  paleostriatal 
system. 

Two  fundamental  syndromes  of  the  corpus  striatum  were 
therefore  recognized,  based  upon  the  differences  of  function 
of  these  two  cellular  systems. 

This  conception  of  the  function  of  the  corpus  striatum 
which  the  writer  formulated  in  19 17,  is  not  at  variance  with 
the  other  syndromes  which  have  been  ascribed  to  this  region, 
but  rather  tends  to  reconcile  and  explain  certain  contradic- 
tory features. 


SYMPTOMATOLOGY  33 

The  Vogt  syndrome  based  upon  a  destructive  lesion  of  the 
neostriatum,  is  characterized  by  choreic  and  athetoid  move- 
ments, spastic  diplegia  (without  pyramidal  involvement) 
and  dysarthria. 

In  this  syndrome  both  cell  types  of  the  neostriatum,  the 
small  neostriatal  cells  and  giant  pallidal  cells,  are  the  seat 
of  a  destructive  lesion,  the  clinical  result  of  which  is  an 
admixture  of  the  symptomatology  referable  to  both  sys- 
tems. There  is  muscular  weakness  and  rigidity  associated 
with  choreiform  and  athetoid  movements.  The  choreo- 
athetosis  is  regarded  as  a  choreiform  manifestation  to  which 
has  been  added  a  certain  degree  of  muscular  rigidity,  which 
would  ensue  from  involvement  of  the  motor  cells  of  the 
neostriatum. 

The  Wilson  syndrome,  on  the  other  hand,  based  on  the 
progressive  lenticular  degeneration  produces  a  more  exten- 
sive lesion  of  the  corpus  striatum.  Here  the  paleostriatum 
and  the  neostriatum  are  both  involved,  the  symptoms  of 
which  are  paralysis,  muscular  rigidity,  and  tremor  of  the 
paralysis  agitans  type  associated  with  clonic  and  tonic 
spasms,  and  in  some  cases  involuntary  movements  of  a 
choreiform  and  athetoid  nature. 

Here  again  there  are  evidences  of  involvement  of  the  two 
essential  neuronal  systems  of  the  striatum.  The  paralysis, 
rigidity  and  tremor  are  dependent  upon  involvement  of  the 
pallidal  system,  while  involuntary  motor  disturbances, 
namely,  the  clonic  and  tonic  spasms,  and  choreo-athetoid 
movements  would  be  occasioned  by  a  destruction  of  the 
striopallidal  system. 

The  great  variation  in  the  symptomatology  of  the  corpus 
striatum  is  therefore  dependent  upon  the  relative  degree 
of  involvement  of  these  two  systems.  When  the  neostriatum 
is  chiefly  affected,  the  choreo-athetoid  element  of  the  symp- 
tomatology is  more  in  evidence;  when  the  pallidal  mechanism 
is  chiefly  involved  the  dominant  symptoms  are  those  of 
paralysis  agitans. 

Symptomatology.     Encephalitis  Iethargica  has  given  rise 


34  ACUTE  EPIDEMIC  ENCEPHALITIS 

to  almost  every  possible  variety  and  degree  of  involvement 
of  these  two  fundamental  systems  of  the  striatum. 

These  manifestations  have  been  slight  or  severe,  tranistory 
or  progressive,  general  or  local.  In  addition  many  bizarre 
and  fragmentary  motor  manifestations  have  been  observed 
which  were  probably  also  of  striatal  origin. 

This  study  is  based  on  the  analysis  of  25  cases  in  which 
evidences  of  striatal  involvement  were  present  at  some 
period  of  the  disease. 

Symptoms  referable  to  the  corpus  striatum  occur  very 
frequently  in  the  acute  stage  of  the  disease,  and  are  evidently 
associated  with  an  early  localization  of  the  inflammatory 
process  in  this  region.  They  may  also  appear  at  a  later  period, 
after  all  acute  symptoms  of  the  disease  have  subsided. 
Very  remarkable  is  the  appearance  of  striatal  symptoms  as 
late  sequelae,  weeks  or  even  months  after  apparent  recovery, 
suggesting  a  recrudescence  of  the  infectious  process. 

Striatal  symptoms  are  of  two  types  corresponding  to  the 
two  chief  syndromes  of  the  corpus  striatum,  as  already 
defined. 

There  is  a  pallidal  type,  characterized  by  paralysis  agitans; 
and  there  is  a  neostriatal  type,  characterized  by  choreiform 
movements. 

While  these  two  clinical  syndromes  may  appear  in  pure 
form  there  is  often  an  admixture  of  the  two,  as  a  result  of 
which  many  curious  clinical  pictures  are  produced. 

Mixed  striatal  types  are  characterized  by  a  combination  of 
the  symptomatology  of  both  paralysis  agitans  and  chorea, 
a  mixed  paralysis  agitans-choreiform  type. 

Of  the  two,  the  paralysis  agitans  type  is  the  more  frequent 
and  usually  the  more  severe  in  its  manifestations.  This  is 
probably  due  to  the  course  and  relations  of  the  pallidal  sys- 
tem and  the  closer  proximity  of  the  paleostriatum  to  the 
midbrain  which  is  the  chief  center  of  the  inflammatory  area. 
Of  the  25  observations,  18  were  of  the  paralysis  agitans 
type,  4  of  the  choreiform  type,  and  3  were  mixed  striatal 
types. 


SYMPTOMATOLOGY 


35 


Pallidal  Type  (Paralysis  Agitans  Type).  The  paralysis 
agitans  type  is  characterized  by  fairly  acute  involvement 
of  the  voluntary  musculature.  Within  a  brief  period  of  two 
or  three  days,  there  develops  the  typical  muscular  rigidity, 
postural  deformities,  mask-like  expression  of  the  face  and  the 
paralytic  disturbances  of  motility  characteristic  of  paralysis 
agitans. 


Fig.  4.  Corpus  striatum;  presenile  paralysis  agitans.  Note  diminution 
of  the  fiber  network  of  the  globus  pallidus.  The  internal  capsule  is  well 
preserved. 


Generally  speaking  the  tremor  is  much  less  constant  and 
when  present  less  conspicuous  than  in  true  paralysis  agitans. 
This  is  probably  caused  by  the  sudden  development  of  mas- 
sive rigidity  which  masks  the  tremor,  producing  the  clinical 
type  known  as  paralysis  agitans,  sine  tremore. 

When  tremor  is  demonstrable  at  this  stage  it  is  usually 
slight  and  localized  in  the  tongue,  face  or  hands.  The  char- 
acteristic pill  rolling  movement  which  we  associate  with 
paralysis  agitans  is  quite  rare  and  I  have  only  observed  it  as  a 


36  ACUTE  EPIDEMIC  ENCEPHALITIS 

late  residual  symptom  in  2  cases,  and  never  in  the  acute 
stage. 

One  side  is  frequently  more  affected  than  the  other,  and 
hemilateral  types  are  encountered  in  a  late  stage  of  the  disease. 
Even  more  limited  forms  occur  (segmental  types),  as,  for 
example,  isolated  involvement  of  the  face  (the  Parkinsonian 
mask).  Involvement  may  also  be  limited  to  the  upper  or 
lower  extremities.  Segmental  types  I  have  only  observed 
after  the  subsidence  of  the  acute  stage,  as  a  late  residual 
manifestation. 

The  tremor  may  show  a  similar  limitation  and  typical 
rhythmical  tremor  may  be  hemilateral  or  sometimes  seg- 
mental, i.  e.,  confined  to  the  head,  an  arm  or  a  leg.  These 
fragmentary  clinical  types  are  usually  encountered  only  as 
late  or  residual  symptoms. 

The  rhythmical  tremor  when  present  is  often  coarse  and 
increased  by  movement.  It  is  then  an  action  tremor,  and  is 
increased,  not  diminished,  during  the  passage  of  a  move- 
ment. In  this  respect  it  differs  from  the  classical  tremor  of 
paralysis  agitans,  but  is  very  similar  to  what  has  been  ob- 
served in  the  earlier  stages  of  the  juvenile  paralysis  agitans 
(primary  atrophy  of  the  pallidal  system). 

True  paralysis  agitans  is  produced  by  a  progressive  lesion 
of  the  pallidal  system,  which  is  atrophic  or  degenerative  in 
nature,  while  the  paralysis  agitans  of  encephalitic  origin  is 
merely  a  symptomatic  manifestation  due  to  injury  of  the 
pallidal  system  by  inflammatory  lesions  or  toxins.  As  the 
acute  lesions  subside,  the  clinical  symptoms  disappear,  which 
explains  the  often  rapid  improvement  in  this  group  of 
cases.  We  are  not  accustomed  to  this  favorable  outcome  in 
true  paralysis  agitans,  which  is  a  progressive  disorder. 
Recoveries  are,  however,  noted  after  inflammatory  lesions 
affecting  other  motor  systems,  and  it  is  only  interesting 
to  note  that  the  pallidal  system  is  no  exception  in  this 
respect. 

A  cataleptic  type  of  encephalitis  has  also  been  described. 
The  association  of  general  muscular  rigidity  of  the  paralysis 


SYMPTOMATOLOGY 


37 


agitans  type  with  the  peculiar  lethargy  characteristic  of 
epidemic  encephalitis  produces  a  clinical  picture  closely 
resembling  catalepsy  fflexibilitas  cerea). 

Abortive  Type.  It  is  also  interesting  to  note  that  in  the 
acute  stage  of  the  disease  mild  transitory  striatal  symptoms 
are  sometimes  present.  These  consist  of  a  certain  tightness  or 
tenseness  of  the  musculature,  a  certain  monotony  and  mild 


%v, 


V. 


Fig.    5.     Presenile    paralysis    agitans.    Vertical    section    through    middle    of 
corpus  striatum,  showing  thinning  of  the  ansa  Ienticularis. 

fixity  of  expression,  with  slight  tremors  of  the  tongue,  face  or 
extremities  which  disappear  as  the  acute  symptoms  subside. 

Progressive  Type.  A  tendency  to  progression  in  the 
paralysis  agitans  group  is  not  uncommon.  In  my  experience 
this  tendency  has  been  greater  in  those  cases  in  which  the 
symptoms  make  their  appearance  late  in  the  disease,  or  as 
relapses  after  improvement  or  apparent  recovery.  It  would 
appear  to  depend  upon  a  renewal  of  the  inflammatory 
process,  or  an  actual  lighting  up  of  old  lesions. 

A  relapsing  form,  unfortunately  not  uncommon,  is  a  well- 


38  ACUTE  EPIDEMIC  ENCEPHALITIS 

recognized  type  of  the  disease.  Its  existence  has  been  em- 
phasized by  von  Economo,  Buzzard  and  Greenfield. 

Pallido-Pyramidal  Types  of  Encephalitis.  In  previous 
studies  of  the  symptomatology  of  the  efferent  pallidal 
system  of  the  corpus  striatum  by  Ramsay  Hunt,  attention 
was  directed  to  the  existence  of  pallido-pyramidal  types  of 
palsy.  This  form  is  characterized  by  a  combination  of  the 
symptoms  of  both  spastic  paralysis  (pyramidal  tract  system) 
and  paralysis  agitans  (pallidal  system),  and  is  by  no  means 
uncommon  because  of  the  close  anatomical  relationship 
of  the  internal  capsule  and  the  corpus  striatum. 

In  pallido-pyramidal  types,  the  paralysis  is  more  complete 
because  both  the  pyramidal  and  extrapyramidal  systems  are 
involved;  the  one  controlling  isolated  synergic  movements  of 
cortical  origin,  and  the  other  striatal  movements  of  the 
automatic  associated  type.  The  muscular  hypertonicity  is 
also  greater  and  combines  the  peculiar  features  of  spasticity 
and  paralysis  agitans  rigidity.  Especially  characteristic  of  the 
pallido-pyramidal  type  are  exaggerated  tendon  reflexes, 
clonus  and  the  Babinski  phenomena  of  the  spastic  type  in 
conjunction  with  a  loss  of  automatic  associated  movements 
of  the  striatal  type.  It  is  rather  remarkable  that,  in  this 
series  of  25  cases  of  striatal  encephalitis,  definite  involvement 
of  the  pyramidal  tracts  was  noted  in  only  3  cases. 

This  is  all  the  more  peculiar  as  we  are  dealing  with  a  rather 
diffuse  disseminated  inflammatory  reaction,  a  type  of  lesion 
which  one  would  naturally  expect  to  involve  the  adjacent 
pyramidal  system  of  the  internal  capsule  and  pes  pedunculi. 
It  is  possible  that  certain  toxins  of  encephalitis  may  possess 
a  special  affinity  for  the  cellular  systems  of  the  striatum, 
which  render  it  particularly  susceptible  to  the  infection. 

The  Neostriatal  Type  (Choreiform  Type).  The  other 
essential  syndrome  of  the  corpus  striatum  which  may  develop 
as  a  result  of  epidemic  encephalitis  is  chorea.  The  choreiform 
movements  of  striatal  origin  are  involuntary  and  irregular 
in  character  and  are  of  the  automatic  associated  type.  Ac- 
cording to  the  view  which  has  already  been  expressed,  they 


SYMPTOMATOLOGY  39 

represent  a  motor  discharge  of  the  striatal  mechanism  in 
contrast  to  paralysis  agitans,  which  is  a  paralytic  mani- 
festation. 

The  choreic  movements  may  be  general,  hemilateral  or 
segmental  (local)  in  their  distribution.  They  may  vary 
somewhat  in  character,  e.  g.,  mild  and  severe,  large  and  small 
amplitude,  and  occasionally  rhythmical.  A  certain  degree  of 
hypertonicity  is  sometimes  present,  giving  an  athetoid 
character  to  the  movement.  Athetosis,  or  choreo-athetosis,  I 
would  regard  as  an  admixture  of  chorea  and  muscular 
rigidity  due  to  involvement  of  both  the  neostriatal  and 
pallidal  systems. 

Acute  Choreiform  Type.  Some  writers  on  the  subject  of 
encephalitis  have  described  cases  characterized  by  gen- 
eralized choreiform  movements  appearing  in  the  acute  stage 
of  the  disease,  associated  with  delirium  and  other  severe 
psychotic  symptoms.  A  clinical  picture  very  similar  to  the 
chorea  insaniens  of  systematic  writers.  Archambault  has 
reported  cases  of  this  type,  as  have  also  Oehmig  in  Munich 
and  Dimitz  in  Vienna. 

Choreo-Athetoid  Types  of  Movements.  In  addition  to 
chorea,  movements  of  an  athetoid  and  choreo-athetoid 
type  may  also  occur,  both  in  the  early  and  late  stages  of  the 
disease;  of  special  interest  is  their  appearance  as  late  sequelae, 
months  after  apparent  recovery.  The  movements  of  this 
type,  like  those  of  chorea,  may  be  general,  unilateral  or 
segmental  (local)  in  distribution.  They  differ  from  chorea  in 
being  slower,  more  stereotyped,  and  associated  with  hyper- 
tonicity of  the  affected  muscles. 

In  the  more  localized  forms  there  is  a  peculiar  repetition 
of  slow  stereotyped  movements  occurring  at  regular  inter- 
vals. These,  except  for  the  limited  and  rather  fragmentary 
character  of  the  movement,  are  very  similar  in  their  character 
to  other  well-known  forms  of  choreo-athetoid  movements  of 
striatal  origin. 

Belonging  to  this  group  are  other  types  of  movement  of 
somewhat  larger  amplitude  which  affect  more  particularly 


4o  ACUTE  EPIDEMIC  ENCEPHALITIS 

the  trunk  and  root  portions  of  the  extremities,  causing 
curious  contortions  of  attitude  and  gait.  Some  of  these 
movements  bear  a  striking  resemblance  to  those  observed  in 
the  dystonia  group  of  motor  disorders,  which,  since  the 
autopsy  report  of  Thomalla  (dystonia  Ienticularis)  must  now 
be  definitely  allied  with  the  symptomatology  of  the  striatal 
body. 

Rhythmical  Chorea  (Bradykinetic  Oscillation).  This  dis- 
order of  motility  varies  somewhat  from  the  recognized 
lenticular  types.  It  is  characterized  by  slow  rhythmical 
movements  of  an  extremity,  sometimes  involving  both  the 
arm  and  leg  on  the  same  side,  and  occurring  with  great 
regularity,  18  to  20  movements  to  the  minute.  With  the 
slow  rhythmical  oscillation  of  the  extremity  there  is  a 
simultaneous  hardening  of  many  of  the  muscles  of  the  arm 
or  leg,  showing  the  diffuse  nature  and  wide  distribution  of 
the  muscular  contractions.  This  form  of  spontaneous  move- 
ment, in  my  opinion,  is  referable  to  the  extrapyramidal 
system  and  in  all  likelihood  to  the  striatal  mechanism.  It 
differs  however  in  the  monotonous  regularity  of  its  syn- 
chronous rhythm  and  stereotyped  repetition  from  other 
forms  of  striatal  movement. 

Marie  and  Levy  have  described  cases  of  this  character  as 
bradykinetic  oscillation,  and  emphasize  the  peculiar  nature 
of  this  type  of  movement  and  its  lack  of  correspondence 
with  any  recognized  clinical  type.  While  agreeing  with  these 
writers  as  to  the  unique  character  of  this  curious  spasmodic 
type,  of  which  4  cases  occurred  in  my  series,  there  is  a  strong 
resemblance  to  certain  types  of  movement  which  I  have  occa- 
sionally observed  in  the  dystonia  musculorum  deformans.  I 
would,  therefore,  regard  it  as  related  to  the  neostriatum. 

Acute  Chorea  of  Childhood  (Chorea  of  Sydenham). 
Before  leaving  the  neostriatal  type,  it  will  be  interesting  to 
mention  some  recent  work  on  the  chorea  of  Sydenham. 
Attention  has  already  been  directed  to  the  fact  that  certain 
well-recognized  types  of  epidemic  encephalitis  were  observed 
in  sporadic  form,  long  before  the  existence  of  the  present 


SYMPTOMATOLOGY  41 

epidemic.  The  question  naturally  arises,  Have  other  clinical 
types  of  infection  of  the  central  nervous  system  a  similar 
origin  and  relationship? 

A  recent  pathological  study  by  Marie  and  Tretiakoff  of 
the  nervous  system  from  a  case  of  chorea  is  very  suggestive 
from  this  point  of  view.  The  case  was  a  typical  one  of  Syden- 
hjW^__chorea,  occurring  in  a  child,  aged  ten,  and  which 
terminated  fatally  ten  days  after  the  onset  of  the  disease. 
Evidences  of  inflammatory  reaction  were  found  throughout 
the  brain  and  spinal  cord,  with  the  exception  of  the  bulb 
and  cerebellum.  The_  neostriatum  and  central  cortex  were 
partioilarly^  affected.  These  investigators,  having  also 
studied  the  "lesions  of  epidemic  encephalitis,  emphasize 
their  great  resemblance  to  those  found  in  the  central  nervous 
system  of  Sydenham's  choreas.  Their  observations  would 
suggest  a  possible  relationship  between  the  acute  infectious 
chorea  of  childhood  and  the  choreic  type  of  encephalitis 
Iethargica.  The  occurrence  of  neostriatal  symptoms  in 
such  a  case,  with  evidences  of  diffuse  involvement  of  the 
nervous  system,  I  would  explain  by  a  special  affinity  of 
the  toxin  for  the  neostriatal  system  of  neurons  (striopallidal 
system). 

Mixed  Striatal  Type  (Mixed  Choreiform  and  Paralysis 
Agitans  Types).  While  the  paralysis  agitans  and  chorei- 
form types  may  occur  in  pure  form,  it  is  well  to  emphasize 
the  fact  that  these  two  clinical  pictures  are  not  infrequently 
combined  in  greater  or  lesser  degree.  Indeed,  among  the 
most  striking  features  of  involvement  are  the  many  bizarre 
combinations  which  combine  both  the  elements  of  chorea 
and  paralysis  agitans. 

Rare  Myoclonic  Types.  Occasionally  one  observes,  after 
an  attack  of  encephalitis,  rhythmical  movements  of  the 
distal  portion  of  the  extremities.  In  one  of  these  cases  which 
presented  typical  symptoms  of  paralysis  agitans,  there  was 
rhythmical  flexion  of  all  the  fingers,  occurring  about  20 
times  a  minute.  Movements  of  this  type  are  so  fragmentary 
that  it  is  rather  difficult  to  localize  them  with  certainty. 


42  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  association  with  paralysis  agitans  and  the  stereo- 
typed regularity  of  the  movement  are  in  favor  of  a  striatal 
origin. 

Rhythmic  twitchings  oj  the  Jace  and  jaw,  either  alone  or  in 
combination,  have  also  been  observed.  When  combined,  the 
movements  of  the  jaw  and  face  may  be  synchronous.  Such 
manifestations  may  represent  disjointed  fragments  of  stria- 
tal motility  or  may  indicate  a  release  of  kinetic  impulses 
in  subsidiary  centers  of  the  pons  varolii  which  contain  the 
motor  nuclei  governing  the  facial  muscles  and  mastication. 

Bilateral  Synchronous  Myoclonia.  There  is  still  another 
type  of  movement  which  has  been  encountered  in  this  dis- 
order, the  classification  of  which  is  somewhat  difficult  in 
the  present  state  of  our  knowledge.  This  is  a  movement  of 
the  myoclonic  type,  involving  a  large  number  of  muscles  and 
causing  bilateral  synchronous  movements  of  the  trunk 
and  root  segments  of  the  extremities  occurring  in  very 
rapid  tempo — 50  to  60  to  the  minute. 

These  movements  differ  from  those  of  the  "myoclonus 
multiplex  type  of  spinal  origin"  in  the  large  number  of 
muscles  which  are  simultaneously  involved,  and  the  extent 
of  the  locomotor  effect.  They  are  also  unlike  those  types  of 
movements  which  we  associate  with  the  striatum. 

Hamill  has  described  a  group  of  cases  representative  of 
this  type,  in  all  of  which  the  movements  were  increased 
during  sleep  in  contrast  to  the  ameliorating  effects  of  sleep 
on  the  pure  striatal  types.  He  suggests  their  relationship 
to  certain  subordinate  motor  centers  in  the  pons  or  medulla, 
which  in  conjunction  with  there  spiratory  center  act  as  auxi- 
liary centers  of  breathing. 

I  have  also  observed  movements  of  this  type.  In  my 
opinion  they  are  neither  cortical  nor  spinal,  and  if  they  do 
not  represent  lower  forms  of  movement  under  striatal 
control  they  are  probably  referable  to  some  infrastriatal 
mechanism  of  the  paleokinetic  system  of  motility. 

Thalamic  Types.  The  optic  thalamus  is  the  sensory  counter- 
part of  the  corpus  striatum.  It  is  the  great  ganglion  station 


SYMPTOMATOLOGY  43 

where  the  neurons  of  the  sensory  paths  terminate  for  their 
final  grouping  and  distribution. 

Some  of  these  neurons  terminate  in  the  optic  thalamus 
itself,  subserving  the  affective  sensibility;  the  great  number 
pass  to  the  sensory  area  of  the  cerebral  cortex  to  subserve 
the  higher  form  of  discriminative  sensibility. 

Lesions  in  this  region  may  produce  sensory  symptoms  of 
the  following  character:  Spontaneous  pain  of  intolerable 
intensity  and  of  persistent  character;  loss  of  superficial  and 
deep  sensibility  with  anesthesia;  ataxia  and  astereognosis. 
There  may  also  be  present  slight  hemiplegia,  as  well  as 
choreic  and  athetoid  movements.  The  sensory  loss  and  pain 
are  alone  of  thalamic  origin,  the  other  symptoms  are  refer- 
able to  surrounding  parts. 

Symptoms  of  thalamic  origin  are  not  infrequent  in  cases  of 
epidemic  encephalitis.  They  are  often  associated  with  evi- 
dences of  striatal  involvement,  but  in  my  experience  are 
neither  so  severe  nor  well  defined.  I  have  observed  no  case 
presenting  the  complete  thalamic  syndrome  as  outlined  by 
Dejerine  and  Roussy.  My  experience  has  been  limited  to 
sensory  symptoms  which  it  seemed  reasonable  to  assume 
were  of  thalamic  origin,  although  one  could  not  deny  their 
possible  relationship  to  the  central  sensory  mechanism  of  the 
spinal  cord  and  brain  stem. 

The  most  frequent  symptom  of  thalamic  involvement  in 
encephalitis,  in  my  experience,  has  been  pain.  This  may  be  of 
agonizing  intensity  and  is  very  resistant  to  all  analgesic 
remedies.  It  may  be  generalized  or  localized  and  may  persist 
for  weeks  or  months.  It  is  difficult  to  differentiate  localized 
thalamic  pains  from  those  referable  to  the  posterior  gray 
matter  and  posterior  root  system  of  the  spinal  cord.  In 
differentiation,  I  would  lay  some  stress  on  the  coexistence 
of  striatal  symptoms  which  would  appear  to  show  inflamma- 
tory involvement  of  both  structures  at  the  same  level. 
In  no  case  have  I  encountered  any  extensive  anesthesia, 
either  superficial  or  deep.  Tactile  sensation  has  shown  little 
or  no  involvement,  and  the  chief  sensory  disturbances  when 


44  ACUTE  EPIDEMIC  ENCEPHALITIS 

present  have  been  of  pain  and  temperature  sensibility.  In 
no  case  was  the  deep  sensibility  affected. 

From  my  personal  experience,  and  that  of  others,  I  am 
inclined  to  believe  that  the  thalamic  symptomatology  is 
largely  limited  to  intractable  and  persistent  pain  associated 
with  mild  evidences  of  sensory  loss,  especially  of  pain  and 
temperature  sensibility. 

As  the  optic  thalamus  is  the  sensory  counterpart  of  the 
corpus  striatum  and  as  both  ganglia  are  closely  connected 
by  short  commissural  systems,  it  is  interesting  to  speculate 
on  the  possible  role  which  irritative  lesions  of  the  thalamus 
may  play  in  the  production  of  striatal  types  of  movements, 
such  as  chorea  and  athetosis.  While  the  facts  of  pathological 
anatomy  point  to  the  neostriatum,  and  especially  the  neo- 
striatal  system  as  the  seat  of  the  essential  lesion  of  chorea, 
it  cannot  be  denied  that  an  irritative  focus  in  the  pallidum 
or  the  thalamus  might  give  rise  to  spontaneous  striatal 
motor  manifestations  of  the  same  character  as  those  result- 
ing from  loss  of  its  inhibitory  mechanism. 

The  following  questions  submitted  to  Dr.  Hunt  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Taylor:  Do  you  make  any  distinction  between  the  two 
parts  of  the  corpus  striatum  in  your  localization  of  these  or  other 
lesions? 

Dr.  Hunt:  I  do.  The  globus  pallidus  is  the  paleostriatum,  and 
the  caudate  nucleus  and  the  putamen  represent  the  neostriatum 
of  comparative  morphologists.  The  small  cell,  neostriatal  system, 
is  related  to  chorea;  the  large  motor  cells,  pallidal  system,  which  I 
associate  with  paralysis  agitans  are  found  in  the  paleostriatum, 
but  they  are  also  present  in  giant  cell  form  in  the  neostriatum. 
Hence  I  conceive  the  corpus  striatum  in  terms  of  cellular  systems 
rather  than  in  terms  of  its  larger  anatomical  constituents.  This 
explains  many  of  the  curious  phenomena  in  the  symptomatology 
of  this  epidemic  and  of  other  striatal  syndromes  with  which  we  are 
familiar. 


SYMPTOMATOLOGY  45 

Dr.  Taylor:  Would  you  regard  a  late  paralysis  agitans  type  as 
a  degeneration  of  the  striata? 

Dr.  Hunt:  No;  I  would  regard  it  as  related  to  a  recrudescence 
of  the  inflammatory  process  rather  than  to  a  slow  degeneration. 
When  paralysis  agitans  develops  after  all  acute  symptoms  have 
subsided,  or  after  an  interval  or  period  of  apparent  temporary 
recovery,  I  would  associate  this  with  an  inflammatory  process — 
a  recrudescence,  a  lighting  up  rather  than  a  slow  degeneration, 
for  the  reason  that  if  it  were  a  degenerative  process  evidences 
of  paralysis  agitans  would  have  been  present  at  once  in  the  acute 
stage. 

Dr.  Taylor:  Is  there  any  evidence  yet  as  to  what  becomes  of  the 
paralysis  agitans  types?  So  far  as  I  have  seen  them  they  have 
steadily  improved,  but  I  have  seen  one  case  which  after  a  year 
seems  to  me  definitely  fixed  in  a  sort  of  paralysis  agitans  condition 
in  part  only.  He  has  the  mask-like  face  of  paralysis  agitans,  but 
he  has  not  got  any  of  the  tremors  or  rigidities.  It  looks  like  a  case 
of  paralysis  agitans. 

Dr.  Hunt:  I  think  the  consensus  of  opinion  is  that  this  group 
of  cases  tends  to  improve,  tends  even  to  get  well.  I  have  had  2  cases 
in  which  after  a  year  there  has  been  rather  a  tendency  to  progres- 
sion and  to  relapses.  Von  Economo  has  reported  the  pathological 
histology  of  such  a  case  in  which  there  was  this  progression,  with 
intervals  of  improvement  and  intermissions  of  both  paralysis 
agitans  and  choreo-athetoid  symptoms.  He  found  post  mortem 
both  old  and  recent  lesions,  which  I  think  proves  beyond  any 
doubt  that  in  some  iorms  of  the  infection  the  old  lesions  may 
come  to  a  standstill  while  the  infective  agent  is  still  active  in  the 
production  of  newer  inflammatory  lesions. 

Dr.  Taylor:  There  are  some  cases  that  suggest  the  segmental 
arrangement  of  the  automatic  mechanism  of  the  brain,  but  there 
are  not  any  cases  of  the  paralysis  agitans  type  that  show  any- 
thing like  a  segmentation,  I  mean  paralysis  agitans  showing 
only  in  the  head  or  arms  or  in  the  legs.  Have  you  seen  anything 
that  suggests  a  segmental  arrangement? 

Dr.  Hunt:  Yes,  I  have  referred  to  this  in  my  paper  as  local  or 
fragmentary  types.  I  have  seen  cases  in  which  the  only  symptom 
of  paralysis  agitans  that  I  could  detect  was  a  very  definite  mask; 
another  case  in  which  there  was  a  paralysis  of  the  "paralysis 
agitans"  or  pallidal  type  of  the  lower  extremities,  not  affecting 


46  ACUTE  EPIDEMIC  ENCEPHALITIS 

the  arms,  and  I  have  also  seen  "paralysis  agitans  tremor"  of  the 
head  with  the  mask,  but  with  no  other  symptoms  of  the  disease 
that  I  could  detect.  . 

Dr.  Tilney:  Does  the  age  of  the  patient  have  any  relation  to' 
the  Parkinsonian  type  or  choreic  type? 

Dr.  Hunt:  I  couldn't  answer  that  very  definitely  except  to  say 
that  I  have  seen  the  paralysis  agitans  type,  or  what  I  thought  was 
the  paralysis  agitans  type,  at  the  age  of  two ;  and  of  course  in  the 
present  epidemic  it  has  not  been  uncommon  in  young  people 
from  eleven  to  fifteen.  In  this  respect  it  is  interesting  to  mention 
that  ten  years  ago  there  was  described  a  case  of  paralysis  agitans 
resulting  from  encephalitis  in  the  Bristol  Infirmary.  Frequent 
mention  has  been  made  in  this  meeting  of  the  sporadic  occurrence 
of  various  clinical  types  in  previous  years.  It  is  interesting  to  know 
that  this  is  true  of  the  paralysis  agitans  type. 

Dr.  Abrahamson:  Why  use  the  term  "paralysis  agitans" 
to  cover  all  the  movements  not  choreiform? 

Dr.  Hunt:  I  use  the  terms  "Parkinsonian"  or  "paralysis  agi- 
tans" because  they  are  so  fixed  in  the  description  of  this  particular 
group  of  symptoms.  I  have  suggested  and  prefer  the  term  pallidal 
to  denote  this  fundamental  type  of  striatal  palsy.  This  term 
denotes  the  relation  of  the  palsy  to  the  pallidal  system  of  the 
corpus  striatum  and  is  analogous  to  the  use  of  the  term  pyramidal 
type  of  palsy,  when  the  pyramidal  tract  or  system  is  involved. 
When  both  motor  systems,  namely,  that  of  the  corpus  striatum 
and  internal  capsule  are  simultaneously  involved,  as  so  frequently 
occurs  in  vascular  lesions  in  this  region,  this  I  would  term 
a  pallido-pyramidal  type  of  palsy. 

Dr.  Patrick:  Do  you  think  that  all  the  abnormal  movements 
arising  from  lesions  of  the  striatal  region  can  be  classified  either 
under  the  paralysis  agitans  or  the  choreiform  types? 

Dr.  Hunt:  I  do.  The  existence  of  an  admixture  of  these  two 
types  or  syndromes  must  however  be  recognized,  namely,  symp- 
toms of  paralysis  agitans  associated  with  those  of  chorea  in  various 
combinations  and  degree. 

A  Member:  I  want  to  bring  out  whether  in  the  various  autopsies 
made  in  this  particular  encephalitis,  anyone  has  investigated  them 
to  see  whether  the  small  cells  are  affected  in  the  choreiform  type 
and  the  other  cells  in  the  Parkinsonian  type  of  disease — whether  it 
is  actually  demonstrated  or  by  analogy  with  what  we  already  know. 


SYMPTOMATOLOGY  47 

Dr.  Hunt:  No;  this  selective  involvement  has  not  been  demon- 
strated in  encephalitis,  but  only  in  certain  types  of  paralysis 
agitans  and  in  Huntington's  chorea.  For  example,  in  a  case  of 
acute  chorea  of  childhood  (Sydenham's  chorea)  reported  by 
Marie,  he  finds  lesions  in  their  essential  character  similar  to  those  of 
epidemic  encephalitis.  Those  lesions  were  not  limited  by  any  means 
to  the  corpus  striatum.  They  were  present  in  but  not  confined  to 
the  neostriatum,  and  yet  the  essential  symptom  is  chorea.  This 
would  suggest  that  the  particular  form  of  infection  which  produces 
the  acute  chorea  of  childhood  has  a  selective  action  on  the  small 
inhibitory  cells  of  the  neostriatum  and  that  this  action  is  toxic 
in  its  nature;  and  while  there  are  small  scattered  foci  of  inflamma- 
tory reaction  throughout  the  central  nervous  system  the  chief 
effect  of  the  toxin  by  virtue  of  this  selectivity  is  concentrated  on 
the  neostriatum.  This  special  selective  action  of  the  toxin  on  certain 
limited  groups  of  cells  or  neurons  is  manifested  in  other  clinical 
types  of  epidemic  encephalitis,  e.  g.,  the  myoclonic  type. 

Clinical  Aspects  of  Non-Purulent  Infections  of  the 
Cerebellum  (J.  P.  Crozer  Griffith).  Undoubtedly  the 
epidemic  of  lethargic  encephalitis  has  exhibited  cases  in 
which  the  process  had  affected  especially  the  cerebellum  and 
adjacent  parts  of  the  brain  more  than  the  cerebrum;  but  the 
vastness  of  the  literature  on  the  subject  of  this  disease 
prevented  any  collection  of  cases  of  this  sort. 

The  author  had  had  under  his  care  4  cases  of  encephalitis 
in  which  the  cerebellum  had  suffered  very  decidedly  from  the 
attack;  indeed,  in  most  of  them  bearing  the  brunt  of  it. 
There  was  great  variety  in  the  symptoms;  but,  basing  the 
description  of  what  might  be  called  a  typical  case  upon  those 
observed  by  him,  and  upon  the  reports  obtained  from  medical 
literature,  it  might  be  said  that  the  principal  acute  symptoms 
consisted  of  unconsciousness  and  absence  of  speech,  with 
later  a  very  decided  ataxia  of  the  limbs,  and  often  of  the 
head  and  trunk,  at  first  usually  interfering  entirely  with 
walking  or  even  with  standing.  Unconsciousness  was  re- 
ported in  more  than  half  of  the  cases.  Although  this  was 
usually  of  brief  duration,  it  sometimes  lasted  for  weeks,  and 
at  times  a  soporose  condition  without  entire  unconsciousness 


48  ACUTE  EPIDEMIC  ENCEPHALITIS 

persisted  for  a  much  longer  time.  In  some  instances,  instead 
of  the  soporose  state,  there  was  violent  screaming,  a  state  of 
fear,  a  maniacal  condition,  and  a  diminution  of  intelligence. 
Even  apart  from  unconsciousness  the  mentality  was  affected 
in  about  two-thirds  of  the  reported  instances.  In  the  cases 
improving  most  rapidly  this  disturbance  of  mentality  might 
last  but  little  more  than  a  week.  In  others  it  sometimes  con- 
tinued for  months,  or  even  to  some  degree  for  years.  Dis- 
turbance of  speech  was  nearly  always  present;  and  by  this 
was  meant  a  disturbance  apart  from  the  loss  of  speech 
due  to  unconsciousness.  With  improvement  of  the  general 
condition  the  speech  returned,  but  was  often  drawling,  slow, 
jerky,  or  affected  in  some  other  way.  In  a  few  instances, 
speech  was  entirely  absent  for  months.  Even  in  the  milder 
cases  the  return  of  perfect  control  of  speech  was  sometimes 
quite  slow,  the  disturbance  still  being  present  in  some 
instances  over  three  years  after  the  attack.  Ataxia  was 
observed  in  all  the  cases,  and  was  usually  an  early  and  promi- 
nent manifestation.  Sometimes  the  gait  was  typically 
drunken.  The  arms  were  involved  also  in  most  instances. 
Generally,  the  power  to  walk  was  regained  in  a  few  weeks, 
although  the  gait  was  far  from  perfect.  The  other  symptoms 
which  have  been  reported  are  oftener  absent  than  present, 
and  cannot  be  called  entirely  characteristic,  although  sug- 
gestive. Among  them  may  be  mentioned  nystagmus  and 
vertigo.  The  former  is  sometimes  very  marked. 

The  immediate  causes  of  the  disease  have  been  varied. 
Some  infectious  disorder  directly  preceded  the  attack  in 
about  two-thirds  of  the  cases.  In  one  instance,  trauma  was 
reported  as  an  immediate  precursor;  in  another,  dysentery. 

The  nature  of  the  disease  is  of  great  interest.  It  is  appar- 
ently without  doubt  an  encephalitis,  and  also  one  which  is 
not  limited  to  any  one  portion  of  the  brain.  Symptoms  other 
than  those  supposedly  cerebellar  have  been  seen  in  prac- 
tically every  case.  Fever,  unconsciousness,  delirium,  con- 
vulsions, and  the  like,  indicate  the  involvement  of  some 
portion  of  the  brain  other  than  the  cerebellum.  The  absence 


SYMPTOMATOLOGY  49 

of  speech  as  the  case  progresses  is  due,  apparently,  to  a 
lack  of  control,  but  early  in  the  attack  it  probably  depends 
upon  unconsciousness  or  some  other  disordered  mental  state. 
It  would  appear  to  be  clear  that  the  cases  upon  which 
this  report  is  based  cannot  be  said  to  have  been  due  to  any 
specific  micro-organism.  The  fact  that  but  one  case  came  to 
autopsy,  and  this  many  years  after  the  attack,  prevented 
any  actual  determination  of  the  lesions  which  were  present 
during  the  acute  condition.  The  prognosis  in  general  is  good, 
at  least  so  far  as  life  is  concerned;  but  the  ultimate  condition 
of  the  patient  is  uncertain.  Some  cases  are  on  record  which 
show  that  final  complete  recovery  may  take  place,  even 
though  the  symptoms  have  lasted  for  several  years.  A  total 
duration  of  three  or  four  months  may  be  taken  as  an  average 
for  the  more  acute  symptoms.  Although  it  is  probable  that 
from  one-third  to  one-half  of  the  cases  may  be  said  to  have 
recovered  completely,  a  number  of  instances  in  the  list 
indicated  that  there  is  decided  danger  of  some  symptoms 
remaining  permanently,  and  among  these  is  especially  to  be 
noted  a  persistence  of  some  degree  of  mental  defect. 

The  following  questions  submitted  to  Dr.  Griffith  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Taylor:  Would  you  regard  the  symptoms  in  these  cases  as 
predominantly  cerebellar? 

Dr.  Griffith:  I  would,  decidedly. 

Dr.  Taylor:  So  that  you  may  in  justice  assume  that  there  were 
actual  lesions  of  the  cerebellum  in  these  cases? 

Dr.  Griffith:  I  think  so. 

Dr.  Weisenburg:  What  is  the  nature  of  the  speech  disturbances? 

Dr.  Griffith:  It  was  irregular  or  jerky  or  slow,  sometimes 
just  an  irregular  speech.  As  it  improved  it  became  more  regular 
but  still  slow;  the  child  had  to  wait  a  bit  before  it  could  enunciate. 

Dr.  Weisenburg:  In  what  way  would  the  cases  differ  from  the 
other  types  of  encephalitis  with  which  you  have  come  in  contact? 

Dr.  Griffith:  You  mean  not  cerebellar?  They  differed  in  their 
4 


5o  ACUTE  EPIDEMIC  ENCEPHALITIS 

irregular  speech  and  particularly  in  the  ataxia.  There  were  no 
other  positive  symptoms;  there  were  suggestive  symptoms. 

Dr.  Weisenburg:  In  other  words,  you  made  the  diagnosis  on 
the  obstructed  speech  and  the  ataxic  movements  of  the  arms  and 
legs  in  the  case? 

Dr.  Griffith:  Yes. 

Dr.  Sachs:  May  I  ask  Dr.  Griffith  whether  he  has  seen  in 
children  distinct  cerebellar  cases  beginning  in  very  acute  fashion 
and  during  the  time  of  the  epidemic,  or  whether  he  knows  about 
such  cases  in  which  the  cerebellar  symptoms  have  been  as  definite 
as  they  could  possibly  be?  I  am  referring  especially  to  such  cases 
in  which  the  child  in  a  very  acute  fashion  shows  no  other  symptom 
except  an  absolute  inability  to  stand  or  walk.  I  remember  one  case, 
for  instance,  where  the  child  had  to  walk  around  by  the  wall 
instead  of  crossing  the  room.  I  want  to  know  whether  any  such 
cases  have  come  to  your  attention  without  any  cerebral  symptoms? 

Dr.  Griffith:  One  of  my  cases  began  with  ataxia — tumbled 
down  the  stairs — came  on  all  of  a  sudden,  and  according  to  the 
parents'  report  there  was  no  history  whatever  of  any  cerebral 
involvement  of  any  kind  that  we  could  find  with  the  exception  of 
her  ataxia,  and  that  disappeared  completely.  She  came  to  my  office 
at  my  request  a  year  or  two  later  and  everything  seemed  to  be  gone. 
That  was,  however,  not  the  epidemic  type.  The  only  one  I  have 
seen  in  connection  with  the  epidemic  had  distinctly  cerebral 
symptoms  as  well,  more  marked  than  the  cerebellar. 

Dr.  Barker:  Were  Dr.  Griffith's  cases  coincident  with  influenza 
outbreaks  or  poliomyelitis  outbreaks?  And  if  he  saw  one  of  those 
cases  today,  could  he  differentiate  it  from  epidemic  encephalitis 
or  would  he  take  it  to  be  encephalitis? 

Dr.  Griffith:  I  could  not  differentiate  it  because  I  think  it  is 
only  a  matter  of  position.  I  think  the  lesion  would  produce  much 
the  same  symptoms. 

Auditory  and  Vestibular  Lesions  (Isidore  Friesner). 
The  following  clinical  studies  are  based  upon  6  cases  of 
epidemic  encephalitis  in  which  the  manifestations  were 
wholly,  or  in  large  part,  due  to  disturbances  of  the  auditory 
or  vestibular  apparatus.  Four  of  these  cases  were  observed 
by  me  in  the  past  two  and  a  half  years.  For  the  histories  of 
the  2  remaining  cases  I  am  indebted  to  my  colleagues.  It 


SYMPTOMATOLOGY  51 

must  be  apparent,  at  a  glance,  that  general  conclusions 
regarding  this  phase  of  the  disease  cannot  be  well  drawn 
from  so  meager  clinical  material,  and  yet  the  almost  total 
absence  of  similar  studies  in  the  literature  is,  in  itself,  suffi- 
cient justification  for  this  survey. 

After  a  fairly  thorough  search  of  the  literature  regarding 
this  disease  I  have  been  impressed  with  the  comparative 
rarity  of  involvement  of  the  eighth  nerve.  I  have  been 
able  to  examine  the  records  of  145  cases  of  epidemic  en- 
cephalitis treated  at  Mt.  Sinai  Hospital  during  the  last  two 
years.  Among  these  there  was  one  instance  of  bilateral  total 
deafness.  In  many  the  stupor  and  the  consequent  lack  of 
cooperation  made  complete  functional  ear  tests  impossible. 
However,  with  the  exception  cited  above,  there  was  no  other 
evidence  of  eighth  nerve  involvement. 

Barker,  in  his  report  of  8  cases,  mentioned  tinnitus  as  a 
symptom  but  once.  Here  the  ears  and  presumably  both  the 
auditory  and  vestibular  apparatus  were  normal.  Eagleton 
reports  a  similar  case  with  tinnitus  and  normal  hearing. 
In  Tilney's  20  cases  there  is  no  mention  of  auditory  or 
vestibular  manifestations.  In  Skversky's  10  cases  the  ears 
were  normal.  In  Hall's  analysis  of  16  cases  there  is  one  with 
vertigo  and  tinnitus.  Functional  tests  are  not  recorded,  but 
the  general  manifestations  of  the  disease  were  far  more 
severe  than  those  of  any  of  the  cases  observed  by  me.  Occa- 
sionally, one  meets  with  recorded  evidences  of  a  disturbance 
in  the  vestibular  apparatus,  as  in  Alexander's  Case  II, 
where  a  vertical  nystagmus  upwards  was  present.  Case  IV 
of  the  series  here  reported  showed  a  similar  phenomenon  due 
undoubtedly  to  a  lesion  in  the  pons.  Mills  and  Wilson  also 
report  a  case  with  vertical  nystagmus  upwards.  Alexander 
and  Allen  reviewed  182  cases  in  the  literature,  and  selected 
100  from  that  number  as  being  typical.  In  their  analysis 
of  the  symptomatology  of  these  cases  there  is  no  mention 
made  of  eighth  nerve  involvement. 

Most  of  the  cases  in  this  series  lacked  some  of  the  cardinal 
symptoms    of   epidemic    encephalitis.    Thus,    in    only    one 


52  ACUTE  EPIDEMIC  ENCEPHALITIS 

instance  was  there  either  lethargy  or  asthenia.  Cases  of  the 
type  reported  here,  several  of  them  with  exceedingly  cir- 
cumscribed lesions,  probably  represent  a  very  mild,  or  even 
an  abortive  form  of  the  disease.  Yet  it  has  seemed  that  in  all 
the  cases  the  diagnosis  was  well  established.  An  explanation 
of  some  of  the  cases  on  a  basis  of  toxicity  has  been  offered. 
One  case  was  originally  reported  as  an  instance  of  botulism. 
Hall,  however,  has  pointed  out  that  the  Cinderella  foot  of 
botulism  will  not  fit  into  the  glass  slipper  of  this  syndrome, 
and  in  the  light  of  our  later  knowledge  it  must  be  considered 
a  case  of  epidemic  encephalitis  with  typical  multiple  lesions. 
Toxic  agents  may  cause  an  endemic,  rarely  an  epidemic; 
never  a  pandemic. 

Case  I.  School-boy,  aged  nine.  On  April  30,  1920,  he  complained 
of  tinnitus  in  the  left  ear,  followed  by  vertigo,  vomiting,  and  diffi- 
culty in  walking.  His  temperature  was  never  over  ioo°F.  On 
May  3rd,  examination  showed  no  tympanic  disease  on  either  side. 
Normal  hearing  right;  total  deafness  left.  There  was  slight  sponta- 
neous nystagmus  to  the  right  and  a  positive  Romberg.  The 
direction  of  the  falling  was  toward  the  left,  but  could  be  influenced 
by  changing  the  position  of  the  head.  In  the  interval  between 
May  3rd  and  May  10th,  the  date  of  the  second  examination, 
a  lumbar  puncture  was  done.  The  fluid  was  clear,  containing  no 
cells,  and  no  excess  globulin.  On  May  10th,  falling  was  no  longer 
regularly  toward  the  left  and  could  not  be  influenced  by  changing 
the  position  of  the  head.  The  total  deafness  persisted.  The  left 
static  labyrinth,  however,  was  normally  irritable  calorically,  and 
there  was  normal  vertigo  and  normal  past  pointing  following 
stimulation.  On  May  19th,  with  a  noise  apparatus  in  the  right 
ear,  patient  heard  26  double  vibrations  but  not  2048  (Cd).  On 
June  5th,  with  a  noise  apparatus,  he  heard  a  forced  whisper: 
heard  26,  and  June  26th  he  heard  ordinary  conversation.  The  upper 
and  lower  tone  limits  are  normal.  The  Weber  is  referred  to  the 
head.  At  this  time  he  showed  a  peculiarity  which  has  persisted  to 
date,  i.  e.,  with  a  noise  apparatus  in  his  right  ear,  when  one  whistles 
with  the  lips,  he  interprets  the  sound  as  a  grunt.  Asked  to  imitate 
the  sound,  he  reproduces  the  pitch  of  the  tone  accurately,  but  has 
no  idea  of  its  quality. 


SYMPTOMATOLOGY  53 

Remarks.  This  is  an  instance  of  total  loss  of  function  of 
the  auditory  branch  of  the  eighth  nerve  with  what  was 
perhaps,  in  the  beginning,  a  collateral  edema  of  the  vestibular 
branch.  The  slight,  if  any,  loss  of  function  in  the  vestibular 
branch  disappeared  rapidly.  Some  hearing  returned  in  about 
three  weeks  from  the  onset  of  the  disturbance.  It  is  now, 
however,  about  seven  months  since  the  beginning  of  the 
attack,  and  it  appears  that  we  are  justified  in  concluding 
that  a  total  restitution  of  hearing  in  the  left  ear  will  not 
occur. 

Case  II.  A  jeweler,  aged^  forty- two;"  never^  had  any  previous 
ear  trouble.  Was  seized  suddenly  four  days  ago  with  tinnitus  and 
deafness  in  the  right  ear.  Slight  pain,  no  vertigo.  There  was  no 
tympanic  disease.  Weber  was  referred  to  the  left.  Rinne,  left 
side  plus,  right  side  minus  ad  infinitum.  The  hearing  in  the  left 
ear  for  voice,  whisper,  watch,  etc.  was  normal.  The  tone  limits 
were  normal.  The  right  ear  was  totally  deaf.  There  was  no  spon- 
taneous nystagmus,  no  falling,  no  past  pointing.  Rotation  to  the 
right  and  to  the  left  was  followed  by  a  nystagmus  of  good  ampli- 
tude lasting  twenty-five  seconds.  Vertigo  and  past  pointing  were 
normal.  Caloric  of  both  right  and  left  labyrinth  positive  in  forty- 
five  seconds.  Both  the  vertical  and  horizontal  canals  were  active 
on  both  sides.  Blood  and  spinal  fluid  Wassermann,  negative. 
Spinal  fluid  was  under  moderate  pressure,  clear,  no  cells,  plus  1 
globulin.  After  the  lumbar  puncture  there  appeared  a  weakness 
of  the  right  facial  of  the  central  type,  and  right  Babinski  and 
Oppenheim.  All  these  symptoms  disappeared  rapidly,  and  in 
July  it  was  reported  that  the  man  had  normal  hearing. 

Case  III.  That  there  are  degrees  of  disturbances  without 
total  loss  of  function  is  illustrated  by  Case  III.  S.  G.,  married; 
family  and  personal  history  have  no  bearing  on  present  illness. 
Patient  was  in  good  health  up  to  four  days  ago.  At  that  time  he  had 
an  attack  of  diplopia.  A  few  days  later  there  was  some  paresis  of 
the  facial  muscles  on  the  left  side.  He  was  tired  and  drowsy. 
Spinal  fluid  was  obtained  under  normal  pressure.  Cell  count  was 
normal,  and  no  excess  of  globulin  was  detected.  Hearing  on  the 
right  side  was  diminished  to  about  one-half  of  what  was  present  on 
the  left  side.  The  Rinne  was  positive,  and  he  localized  the  Weber 
to  the  left  ear. 


54  ACUTE  EPIDEMIC  ENCEPHALITIS 

Remarks.  Taylor  also  reports  a  case  with  a  bilateral 
disturbance  of  hearing  of  the  nerve  type. 

Tinnitus  is  a  symptom  occasionally  met  with  in  lethargic 
encephalitis.  Eagleton,  however,  has  shown  that  tinnitus 
may  occur  in  such  a  case  with  no  demonstrable  disturbance 
in  hearing.  Grahe,  in  his  studies  of  the  internal  ear  in  lethar- 
gic encephalitis,  states  that  in  6  of  the  13  cases  examined,  the 
bone  conduction  was  shortened.  It  is  especially  noteworthy 
that  a  case  with  shortening  of  bone  conduction,  but  other- 
wise with  normal  findings,  presented  a  perfectly  normal 
duration  of  hearing  by  air  conduction.  Grahe  is  under  the 
impression  that  there  is  no  relationship  between  this  condi- 
tion and  meningeal  changes,  since  shortened  bone  conduction 
occurred  both  in  cases  with  normal  cerebrospinal  fluid,  and 
in  others  with  pathological  changes  in  the  spinal  fluid. 

Case  IV.  A  dentist,  aged  thirty-six,  was  seized  with  vertigo, 
nausea,  vomiting,  deafness  in  left  ear,  diplopia  and  ataxia  which 
confined  him  to  his  bed  for  one  week.  He  had  no  fever.  He  was 
unable  to  leave  his  home  or  to  attend  to  his  professional  duties 
for  several  weeks,  so  that  by  the  time  he  was  seen  during  the  fourth 
week  of  his  illness,  many  of  his  earlier  symptoms  had  disappeared. 
The  history,  in  addition  to  the  above,  was  that  his  blood  Wasser- 
mann  was  negative.  His  cerebrospinal  fluid  showed  no  cells, 
globulin  content  normal,  Wassermann  negative.  The  otological 
tests  were  as  follows.  Weber  is  referred  to  the  head.  Rinne,  both 
sides  positive.  Schwabach,  slightly  shortened  both  sides.  The 
upper  and  lower  tone  limits  are  normal  for  both  ears.  Tested  with 
a  noise  apparatus,  both  ears  hear  low  conversation  readily.  With 
the  exception  of  the  slightly  shortened  Schwabach,  the  hearing 
of  both  ears  is  normal.  Static  Labyrinth.  Station  is  good,  very  little 
swaying.  There  is  no  spontaneous  past  pointing  in  the  right  arm; 
the  left  arm  past  points  2  inches  to  the  left.  This  persists  on  repeated 
tests.  There  is  a  spontaneous  nystagmus  of  the  rotary  type  directed 
to  both  sides,  slightly  more  marked  to  the  right.  There  is  also  a 
vertical  nystagmus  upwTard.  Rotation  to  the  right  is  followed 
by  a  horizontal  nystagmus  of  fair  amplitude,  lasting  twelve 
seconds.  Rotation  to  the  left  is  followed  by  a  nystagmus  of  very 
good  amplitude,   lasting  twenty-five  seconds.    Tests  for   Vertigo. 


SYMPTOMATOLOGY  55 

Rotation  to  the  right;  the  right  arm  touches,  the  left  arm  past 
points  1  inch  to  the  left  (spontaneous  past  pointing).  Rotation 
to  the  left;  both  arms  past  point  2  inches  to  the  left.  Caloric 
reaction  of  right  vertical  canals  positive  but  faint,  one  minute 
and  fifteen  seconds.  No  past  pointing  in  either  arm.  Stimulation 
causes  diplopia.  Caloric  reaction  of  the  right  external  (horizontal) 
slightly  more  marked  than  that  of  the  vertical  canals.  No  past 
pointing  in  either  arm.  Caloric  stimulation  of  the  right  external 
canal  arouses  an  oblique  nystagmus  upwards.  Caloric  reaction 
of  left  vertical  canals  positive  faint,  fifty-seven  seconds,  reaction 
of  external  canal  more  marked.  No  past  pointing  in  either  arm. 

Remarks.  The  hearing  is  normal.  There  is  a  spontaneous 
nystagmus  to  both  sides  and  also  upward.  Functional  tests 
show  an  interference  with  all  reactions  following  stimula- 
tion of  the  left  labyrinth.  Caloric  stimulation  of  the  right 
vertical  canals  causes  diplopia,  of  the  right  external  canal 
an  oblique  nystagmus  upwards.  The  nystagmus  following 
stimulation  of  the  right  labyrinth  is  nearly  normal  while  the 
vertigo  is  markedly  suppressed.  These  facts  indicate  that  the 
lesions  are  not  peripheral,  but  are  situated  in  the  brain  stem 
and  probably  in  the  cerebellum  as  well. 

Case  V.  F.  W.,  physician.  Was  seized  about  March  4,  1920, 
with  an  attack  of  vertigo,  nausea  and  vomiting.  On  March  5th  and 
6th  there  was  diplopia.  The  vertigo  continued  for  three  days  and 
gradually  subsided  within  a  week.  Never  any  fever  or  headache. 
At  the  end  of  the  week  he  was  examined.  There  was  no  tympanic 
disease.  The  hearing  of  both  ears  was  normal.  There  was  a  coarse 
rotary  nystagmus  to  the  left.  In  walking  he  swayed  to  the  right, 
and  supported  himself  in  his  right  side.  Unfortunately  no  other 
stimulation  was  applied  to  the  static  labyrinth,  except  rotation. 
This  was  repeated  several  times,  and  showed  definitely  a  total 
loss  of  reaction,  i.  e.,  of  both  nystagmus  and  vertigo  on  rotating 
to  the  left,  whereas  on  rotating  to  the  right  there  was  a  normal 
nystagmus  lasting  twenty-two  seconds,  with  normal  vertigo. 

Remarks.  There  may  be  some  question  as  to  the  validity 
of  the  conclusion  that  we  are  dealing  here,  so  far  as  the 
ears  are  concerned,  with  an  isolated  lesion  of  one  vestibular 


$6  ACUTE  EPIDEMIC  ENCEPHALITIS 

nerve.  It  may  be  remembered,  however,  that  this  patient  fell 
to  the  right,  that  he  supported  himself  on  his  right  side, 
that  he  had  a  typical  rotary  vertigo,  with  objects  moving 
about  to  his  left  and  that  he  had  a  spontaneous  rotatory 
nystagmus  to  the  left.  These  facts,  with  the  results  of  the 
rotation  tests,  seem  sufficient  to  warrant  our  conclusion. 

In  conclusion,  it  may  be  stated  that  lesions  of  the  eighth 
nerve  in  epidemic  encephalitis  are  rare.  This  rarity  may  be 
more  apparent  than  real,  for  Eagleton,  in  his  examination  of 
4  cases,  states  that  he  was  able  to  demonstrate  disturbances 
in  the  vestibular  apparatus  in  every  one  of  the  four. 

The  involvement  may  result  in  a  diminution  of,  or  a  total 
ablation  of  function.  I  have  had  no  personal  experience 
with  lesions  affecting  both  branches  of  the  eighth  nerve 
followed  by  total  ablation  of  function,  but  Mills  and  Wilson 
report  2  such  cases. 

Either  the  auditory  or  vestibular  branch  may  be  involved. 

Judging  from  the  number  of  cases  examined  and  reported, 
there  is  an  unusual  proportion  of  vestibular  lesions.  The 
virus  appears  to  exercise  an  exceedingly  fine  selective 
action. 

Restitutio  ad  integrum  occurs  perhaps  more  frequently  in 
the  vestibularis  than  it  does  in  the  cochlearis. 

The  polioencephalitic  cases,  with  exceedingly  limited  le- 
sions, undoubtedly  represent  an  abortive  type  of  the  disease 
in  which  many  of  the  cardinal  symptoms  of  epidemic  en- 
cephalitis are  lacking. 

The  diagnosis  in  the  absence  of  other  confirmatory  findings 
is  based  upon  the  exclusion  of  middle  ear  disease,  of  tumor, 
the  absence  of  the  usual  serological  findings,  and  other 
evidences  of  syphilis,  and  finally  upon  the  occurrence  of  these 
cases  during  an  epidemic  of  encephalitis  followed  by  fairly 
rapid  recovery. 

The  following  questions  submitted  to  Dr.  Friesner  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 


SYMPTOMATOLOGY  57 

Dr.  Sachs:  Evidently  Dr.  Friesner  himself  has  found  some 
things  entirely  peculiar  to  this  disease? 

Dr.  Friesner:  Yes;  this  one  instance,  which  I  studied  in 
connection  with  Dr.  Strauss,  I  have  been  unable  to  explain 
satisfactorily  to  myself.  It  is  an  exceedingly  curious  phenomenon; 
I  do  not  know  what  it  means.  This  child  is  able  to  reproduce 
accurately  the  tone  of  my  whistle,  but  is  unable  to  grasp  the 
quality  of  the  tone.  In  other  words,  asked  to  reproduce  the  pitch 
he  sings  the  note  accurately,  but  when  I  ask  him,  "What  noise 
did  I  make?"  he  says:  "You  grunted."  I  do  not  think  my  whistle 
is  anything  like  a  grunt.  He  reproduces  the  pitch  but  not  the 
quality.  He  is  an  exceedingly  intelligent  chap,  about  ten  years  old. 

Dr.  Dana:  When  he  reproduced  your  whistle  did  he  whistle 
or  grunt  ? 

Dr.  Friesner:  He  grunts.  I  have  him  close  his  eyes,  and  I 
put  the  noise  apparatus  in  the  ear  with  which  he  hears  normally, 
and  I  whistle.  Then  I  ask  him  what  sound  he  heard  and  he  grunts. 
I  ask  him  to  sing  the  note  and  he  produces  the  pitch  accurately, 
and  he  does  that  whether  my  whistle  is  high-pitched  or  low- 
pitched.  I  never  have  seen  that  before  nor  has  any  other  otologist 
with  whom  I  have  spoken,  but  it  is  really  present  and  there  cannot 
be  any  question  about  it,  because  I  have  tested  him  at  least  four 
or  five  times  since  he  first  showed  this  curious  thing. 

Dr.  Dana  :  You  make  a  diagnosis  of  encephalitis  in  these  cases 
largely  by  exclusion,  do  you  not? 

Dr.  Friesner:  Frankly,  most  oi  the  diagnoses  are  made  by 
the  attending  neurologist  or  physician;  it  is  only  because  of  the 
ear  symptoms  that  I  have  been  asked  to  examine  cases. 

Dr.  Dana:  Nevertheless,  you  concluded  by  giving  the  data  for 
making  a  diagnosis  practically  by  exclusion. 

Dr.  Friesner:  I  did  that.  Of  course,  as  I  have  said,  these  data 
are  so  meager  that  it  is  almost  impossible  to  draw  any  conclusions. 
With  regard  to  the  diagnosis,  that  statement  was  passed  upon  one 
case;  this  case  was  referred  to  me  because  he  had  tinnitus  and 
deafness.  When  I  examined  him  I  noted  that  he  had  none  of  the 
usual  phenomena  which  occur  with  specific  disease,  and  at  once 
it  occurred  to  me  that  it  might  be  an  instance  of  lethargic  enceph- 
alitis. A  subsequent  examination  of  the  man  and  the  development 
of  facial  paralysis  proved  that  my  supposition  was  correct. 

Dr.  Sachs:  You  are  willing  to  believe  that  just  as  there  are 


58  ACUTE  EPIDEMIC  ENCEPHALITIS 

some  cases  of  lethargic  encephalitis  where  there  are  chiefly  eye 
symptoms,  it  may  be  that  some  exhibit  chiefly  ear  symptoms? 

Dr.  Friesner:  Yes.  There  is  one  thing  I  would  like  to  ask.  I 
have  stated  in  my  conclusions  and  have  called  these  cases  "polio- 
encephalitic "  cases.  I  wonder  whether  it  is  not  more  correct  to 
call  them  "polyneuritic."  When  I  looked  to  see  in  what  category 
I  could  place  these  cases,  I  examined  the  divisions  in  your  book 
and  I  found  that  they  fitted  only  into  what  you  called  the"poIio- 
encephalitic  cases,"  but  it  seems  to  me  these  are  nerve  lesions, 
not  nuclear  lesions,  and  I  wonder  whether  "polyneuritis"  is  not 
correct  or  "mononeuritis." 

Dr.  Timme:  May  it  be  central? 

Dr.  Friesner:  I  do  not  know.  There  have  been  very  few  cases 
reported  of  total  deafness  of  central  origin.  I  never  have  heard 
of  them  in  anything  like  an  inflammatory  state  such  as  one  gets 
with  encephalitis. 

Dr.  Dana:  You  mean  you  do  not  get  total  deafness  in  one  ear 
from  a  central  lesion? 

Dr.  Friesner:  There  are  a  few  cases  reported  with  tumor  on 
one  side  and  an  abscess  on  the  other,  or  tumor  on  one  side  and 
hemorrhage  on  the  other,  in  both  lobes. 

Dr.  Dana:  I  mean  a  nuclear  disease  of  the  cochlear  nerve.  Is 
that  not  called  deafness  in  that  ear? 

Dr.  Friesner:  I  am  not  aware  of  any  such  case.  I  do  not  think 
we  can  differentiate  between  a  nuclear  disease,  causing  true  deafness, 
and  a  nerve  disease  that  is  a  true  neuritis. 

Dr.  Strauss:  What  other  disease  could  cause  these  symptoms 
if  not  encephalitis? 

Dr.  Friesner:  The  subsequent  development  of  this  one  case, 
of  which  I  speak,  and  which  came  to  me  with  total  deafness, 
could  not  be  caused  by  anything  else  than  encephalitis,  but, 
this  opinion  may  be  due  to  my  faulty  observation  when  he  came  to 
me.  All  I  was  able  to  determine  was  that  he  was  totally  deaf  in 
one  ear,  and  that  it  had  occurred  but  four  days  previous  to  my 
examination.  That  is  all  he  had — total  deafness.  The  static  laby- 
rinths on  both  sides  were  perfectly  normal.  The  first  case,  and 
I  am  depending  on  your  word,  was  lethargic  encephalitis. 

Dr.  Sachs:  Could  any  other  disease  have  caused  it,  or  do  you 
know  of  any  other  disease? 

Dr.  Friesner:  Not  as  regards  the  first  case. 


SYMPTOMATOLOGY  59 

Ocular  Manifestations  (Ward  A.  Holden).  The 
eye  symptoms  noted  in  one  hundred  consecutive  case 
histories  of  epidemic  encephalitis  at  Mt.  Sinai  Hospital 
are  as  follows: 


A.  Opticus  Symptoms.  Blurring  of  the  optic  discs  in  4, 
papilledema  in  1. 

B.  Oculomotorius  and  Abducens  Symptoms. 

1.  Ptosis.  Of  both  eyes  in  45,  of  one  eye  alone  in  1 1  — 
56  patients  in  all. 

2.  Extrinsic  muscles  of  the  eyeball. 

Paresis  or  paralysis  of  both  external  recti  in  17;  of  the 
right  external  rectus  alone  in  14;  of  the  left  external  rectus 
alone  in  13 — ^44  patients  in  all. 

Paresis  or  paralysis  of  both  superior  recti  in  1,  of  both  in- 
ternal recti  in  4,  of  the  right  internal  rectus  alone  in   1. 

Paresis  of  both  internal  and  both   external  recti  in  2. 

Paralysis  of  all  muscles  supplied  by  one  3d  nerve  in   1. 

Paralysis  of  conjugate  dextroversion  of  both  eyes  in  2. 

In  all,  weakness  of  the  oculomotor  muscles  that  would 
give  rise  to  diplopia  in  56  patients. 
NysW^rnriK  in  32  patients. 

3.  Pupils.  Irregularity  in  15,  inequality  in  20.  Sluggish- 
ness_or_absence  of  light  reflex  in  35  patients,  in  13  of  whom 
the  convergence  or  accommodation  reflex  was  sluggish  also. 

The  irregularity  and  inequality  of  the  pupils  in  28  of  the  35 
cases  were  in  eyes  with  sluggish  pupils,  so  that  irregularity 
and  inequality  not  associated  with  sluggishness  were  noted 
but  7  times. 

4.  Accommodation.  Weakness  of  accommodation  in  both 
eyes  in  1. 

C.  Facialis  Symptoms.  Weakness  of  some  or  all  of  the 
muscles  supplied  by  the  facialis  of  both  sides  in  24,  of  one  side 
in  49      -3  patients  in  all. 

The  most  marked  divergence  from  these  percentages  is  in 
the  carefully  studied  8  cases  of  Barker,  Cross  and  Irwin 


60  ACUTE  EPIDEMIC  ENCEPHALITIS 

(Amer.  J.  M.  5c,  cliv.,  2-3).  They  found  partial  ptosis 
in  3,  sluggish  pupils  in  the  entire  8,  and  weakness  of  accom- 
modation in  4.  Their  reports  on  the  recti  muscles  are  less 
specific. 

The  percentages  in  the  thirty  histories  reported  in  Tilney 
and  Howe's  book  "  Epidemic  Encephalitis,"  are  similar  to  the 
Mt.  Sinai  Hospital  percentages  except  as  regards  the  recti 
muscles.  Tilney  and  Howe  found  the  internal  rectus  paretic 
more  frequently  than  the  external. 

Opticus  Symptoms.  There  was  noted  in  4  patients  at  Mt. 
Sinai  Hospital  a  blurring  of  the  optic  discs  and  in  one  a 
definite  papilledema. 

The  earlier  reports  on  encephalitis  referred  in  many  cases 
to  blurring  of  the  discs.  But  we  recognize  that  a  slight  edema 
and  a  reddening  of  the  discs  due  to  dilatation  of  the  capil- 
laries, with  overfilled  and  perhaps  tortuous  retinal  veins,  is  a 
fairly  common  condition  when  the  general  circulation  is 
sluggish.  In  such  cases  a  subsequent  examination  is  made  and 
if  the  condition  remains  unchanged  we  do  not  regard  it  as  a 
beginning  papilledema  and  we  are  strengthened  in  this 
belief  when  the  patient  complains  not  of  headache  and 
vomiting,  but  merely  of  cold  feet.  It  is  possible  that  some  of 
the  cases  of  blurred  optic  discs  reported  may  have  had  but 
little  significance. 

True  papilledema  was  noted  in  1  Mt.  Sinai  Hospital 
patient  and  was  found  in  1  of  the  20  at  the  Neurological 
Institute.  The  latter  patient,  a  child  three  years  of  age, 
had  meningeal  symptoms,  paresis  of  both  external  recti, 
paresis  of  the  right  facialis  and  right  hemiparesis,  with 
papilledema  of  two  and  a  half  dioptres  elevation  in  each  eye. 
She  made  a  complete  recovery.  In  another  case  with  papill- 
edema, verbally  related,  there  was  found  at  the  autopsy  an 
extensive  subcortical  hemorrhage  in  the  parietal  region 
which  had  caused  hemiplegia. 

True  papilledema  then  is  a  very  rare  symptom  of  enceph- 
alitis and  seems  to  occur  only  where  there  are  unusual  com- 
plications.   This    papilledema    is    doubtless    the    result    of 


SYMPTOMATOLOGY  61 

increased  intracranial  pressure  in  most  cases,  although  in 
some  cases  it  may  be  due  directly  to  meningitis.1 

Oculomotorius  and  Abducens  Symptoms.  Inflamma- 
tory changes  have  been  found  widespread  in  the  brain,  but 
with  great  frequency  in  the  brain  stem,  consisting  of  edema, 
hemorrhage,  proliferation  of  neuroglia,  circumvascular  exu- 
dation of  leucocyte-like  cells,  and  degeneration  of  ganglion 
cells.  The  meninges  also  are  frequently  inflamed.  From  this 
it  is  evident  that  there  may  be  pressure  upon  the  nuclei  of 
the  ocular  nerves,  upon  the  supranuclear  and  infranuclear 
fibers — direct  and  association — and  upon  the  trunks  of  the 
nerves  at  the  base  of  the  brain.  This  pressure  may  be  transi- 
tory or  permanent,  slight  or  destructive,  or  even  alternating 
and  recurrent.  It  is  obvious  that  clinically  one  must  find  in 
this  disease  all  degrees  of  muscular  palsy  and  all  possible 
combinations  and  varieties  of  palsy  of  the  third  and  sixth 
nerves,  with  changes  from  week  to  week. 

1  C.  P.  Symonds  in  a  paper  on  "Optic  Neuritis  in  Encephalitis  Lethargica," 
Lancet,  Dec.  18,  1920,  after  describing  four  cases  studied  at  the  Johns  Hopkins 
Hospital,  gives  as  one  of  his  conclusions  the  following  statement:  "In  the 
association  of  optic  neuritis  with  acute  disseminated  myelitis  we  have  an 
instance  of  involvement  of  the  optic  nerves  in  a  diffuse  inflammatory  process 
affecting  the  nervous  system,  which  is  analogous  to  the  association  of  optic 
neuritis  with  encephalitis  lethargica." 

In  Archives  0/  Ophthalmology,  vol.  xl,  No.  6,  and  vol.  xliii,  No.  3,  I  described 
five  cases  of  optic-nerve  affection  in  acute  disseminated  myelitis.  In  this 
disease  the  affection  of  the  optic  nerve  is  a  localized  inflammation  about 
certain  blood-vessels  in  the  nerve.  There  is,  as  a  rule,  no  elevation  of  the 
disc  and  there  ensues  a  partial  or  general  pallor  of  the  disc,  with  marked 
disturbance  of  vision.  In  3  of  the  4  cases  in  which  visual  tests  could 
be  carried  out  I  found  a  lateral  hemianopic  defect  in  the  field  of  one  eye  only, 
which  seemed  to  me  characteristic  of  the  disease,  and  in  one  case  an  excessive 
concentric  contraction  of  the  field  of  one  eye. 

The  reports  of  optic-nerve  disturbances  in  epidemic  encephalitis  lethargica 
with  which  I  am  familiar,  including  those  of  Symonds,  show  little  in  common 
with  the  optic-nerve  disturbances  I  have  seen  in  acute  disseminated  myelitis. 
Therefore,  until  anatomical  proof  to  the  contrary  is  presented,  I  prefer  to 
regard  the  optic-nerve  disturbances  of  epidemic  encephalitis  as  being  chiefly 
of  the  papilledematous  type  due  to  increased  intracranial  pressure,  rather  than 
of  the  retrobulbar  inflammatory  type,  as  Symonds  would  seem  to  suggest. 


62  ACUTE  EPIDEMIC  ENCEPHALITIS 

In  general,  in  this  disease,  we  find  a  disinclination  to  use 
the  eye  muscles  or  a  quick  fatigue  and  return  to  the  position 
of  rest  after  using  them,  even  when  there  is  no  well  marked 
paresis.  In  this,  as  in  many  disturbed  mental  conditions,  the 
patient  may  dislike  to  look  up  and  may  simulate  paralysis  of 
upward  movement  unless  repeated  tests  are  made. 

Ptosis.  In  the  lethargic  state  the  patient  may  lie  with  his 
eyes  closed  in  the  position  of  rest  and  often  cannot  be  urged 
to  keep  them  open,  or  even  to  open  them  wide  for  a  moment. 
This  may  be  due  to  a  mental  disinclination,  to  photophobia, 
to  a  dread  of  diplopia,  or  to  a  spasm  of  the  orbicularis  palpe- 
brarum muscles,  as  well  as  to  weakness  of  the  levators.  When 
he  can  be  urged  to  open  his  eyes  a  difference  in  the  width  of 
the  palpebral  apertures  may  be  seen  or  a  drooping  of  one  or 
both  upper  lids  may  be  noted,  but  except  in  the  unusual 
cases  of  complete  third  nerve  paralysis,  complete  ptosis  is  not 
likely  to  be  present.  In  other  cases  the  eyes  are  kept  open,  but 
winking  is  infrequent.  Forcible  closing  of  the  eyes  often  leads 
to  a  marked  tremor  of  the  lids,  for  tremor  is  a  very  constant 
symptom  of  encephalitis.  When  one  eye  has  been  kept  closed 
a  few  days  to  prevent  diplopia,  its  palpebral  aperture  will  be 
narrower  than  that  of  the  other  eye  when  both  are  opened. 
One  can  easily  realize  that  the  question  of  ptosis  in  a  given 
case  may  admit  of  a  variety  of  answers.  Ptosis  was  noted  in 
fifty-six  of  the  Mt.  Sinai  Hospital  patients. 

Extrinsic  Muscles  of  the  Eyeball.  Certain  brain  affections 
have  rather  definite  paralyses  of  the  ocular  muscles  which  are 
pathognomonic.  Thus  after  diphtheria  there  may  be  paralysis 
of  accommodation  on  both  sides  without  pupillary  distur- 
bances; in  botulism  there  may  be  ophthalmoplegia  interna 
on  both  sides — that  is,  iridoplegia  and  dilatation  of  the 
pupil  with  paralysis  of  accommodation ;  in  polioencephalitis 
superior  the  two  internal  recti  are  first  paralyzed  and  later 
often  one  or  both  external  recti;  in  destruction  of  one  ab- 
ducens  nucleus  there  is  conjugate  paralysis  of  dextro-  or 
sinistro-version  of  the  two  eyes;  in  red  nucleus  involvement 
there  is  loss  of  upward  movement  of  the  eye;  and  with 


SYMPTOMATOLOGY  63 

exudation  at  the  base  of  the  brain  both  sixth  nerves  or  both 
third  nerves  in  some  or  all  of  their  branches  may  be  affected. 

In  epidemic  encephalitis  almost  all  of  these  paralyses  are 
found.  And  if  there  is  anything  at  all  characteristic  it  is  the 
frequent  association  of  ptosis  with  paralysis  oj  the  external  recti. 
In  the  Mt.  Sinai  Hospital  group  there  were  twenty-three 
patients  in  whom  paralysis  of  one  or  both  external  recti 
(without  accompanying  paralysis  of  internal  recti)  was 
associated  with  ptosis  of  one  side  or  both.  This  is  a  combina- 
tion of  third  and  sixth  nerve  affections  that  is  rarely  met 
with  in  any  other  disease. 

The  fourth  nerve  doubtless  is  affected  at  times  in  enceph- 
alitis, although  paresis  of  the  superior  oblique  muscle  has  not 
been  noted  in  any  reports  recalled.  This  may  be  because 
a  paresis  of  the  superior  oblique  might  easily  be  overlooked  in 
a  lethargic  patient,  and  even  in  a  mentally  alert  patient  it 
might  escape  notice  when  masked  by  more  obvious  palsies  of 
other  motor  muscles. 

There  is  a  curious  condition,  of  whose  pathology  we  are 
ignorant,  known  as  paralysis  of  divergence.  In  this  condition 
there  is  neither  paralysis  nor  spasm  of  the  recti  muscles  and 
the  mobility  of  each  eye  is  normal,  but  the  eyes  are  converged 
on  a  point  some  15  cm.  away  and  see  single  at  this  distance, 
while  at  greater  distances  there  is  homonymous  diplopia  in 
every  direction  of  the  gaze.  The  etiology  of  this  condition  is 
obscure  and  the  lesion  is  supposed  to  lie  in  a  purely  hypo- 
thetical divergence  center.  It  has  been  seen  in  midbrain 
tumor  and  in  uremia.  This  paralysis  of  divergence  was  one  of 
the  earliest  symptoms  in  a  patient  with  encephalitis,  and  two 
colleagues  have  said  that  they  had  found  the  same  condition 
in  encephalitis  patients,  so  probably  it  is  not  very  rare  if  care- 
fully sought  for;  and  study  of  the  cases  in  which  it  is  present 
may  lead  to  our  better  understanding  of  the  condition.1 

1  In  some  cases,  paralysis  of  divergence  has  either  preceded  or  followed 
paralysis  of  one  external  rectus,  suggesting  that  the  site  of  the  lesion  in  this 
condition  lies  near  the  abducens  nucleus. 

It  would  be  natural  to  assume  that  there  is  a  break  in  the  association 


64  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  course  of  these  palsies  is  not  uniform ;  often  they  dis- 
appear in  a  few  days,  sometimes  they  are  permanent,  some- 
times they  are  recurrent.  In  general  we  may  say  that  diplopia 
disappears  early,  ptosis  later,  and  pupillary  anomalies  and 
weakness  of  accommodation  last  of  all  the  eye  symptoms, 
many  months  after  the  onset. 

Nystagmus.  There  may  be  the  slight  nystagmus  of 
asthenic  states  or  the  pronounced  nystagmus  of  organic 
brain  disease.  Very  frequently  too  there  are  the  nystagmoid 
twitchings  in  the  direction  of  action  of  a  muscle  that  is  par- 
etic. One  variety  of  irritative  spasm  that  has  been  described 
to  me  is  a  lightning-like  oscillation  of  the  two  eyes,  without 
parallelism  of  action,  coming  on  at  intervals  when  the  eyes 
are  in  the  position  of  rest.  These  different  varieties  have  not 
been  differentiated  in  our  figures,  but  nystagmus  was  noted 
in  32  of  the  Mt.  Sinai  patients. 

Pupils.  In  35  of  the  100  patients  there  was  ^defective 
light  reaction  of  the  pupils,  often  with  irregularity  and 
inequality.  As  a  rule  in  encephalitis  the  sluggish  pupils  are 
small  or  of  medium  size.  They  differ  from  the  pupils  of 
cerebral  lues  only  in  the  greater  frequency  of  an  accompany- 
ing defective  convergence  reaction.  The  characteristic  pupils 
of  cerebral  lues  are  seen  also  at  times  with  tumors  and  non- 
Iuetic  inflammations  in  the  brain  stem.  In  encephalitis  this 
symptom  is  very  common,  Barker  finding  it  in  every  one  of 
his  reported  cases. 

tract  between  the  abducens  nucleus  of  one  eye  and  the  nucleus  for  the  internal 
rectus  of  the  other  eye.  However,  we  believe  that  the  impulse  which  turns 
both  eyes  to  the  right  arises  from  the  right  abducens  nucleus.  And  if  this 
impulse  were  sent  from  the  abducens  nucleus  in  normal  measure  to  the  right 
external  rectus  and  incompletely  to  the  left  internal  rectus  the  result  would 
be  divergence  of  the  two  eyes  and  not  the  convergence  which  is  found  in  these 
cases.  Could  we  assume  that  the  impulse  which  turns  the  eyes  to  the  right 
arises  from  the  nucleus  of  the  left  internal  rectus,  an  interruption  of  the 
association  fibers  in  the  longitudinal  fascicle  would  prevent  the  full  impulse 
from  reaching  the  right  external  rectus  and  thus  lead  to  convergence  of  the 
eyes.  But  since  this  assumption  seems  untenable,  our  attempts  to  solve  the 
problem  with  our  present  data  are  purely  speculative  and  vain. 


SYMPTOMATOLOGY  65 

This  is  not  the  place  to  discuss  the  mechanism  and  manner 
of  production  of  the  Argyll-Robertson  pupil,  but  it  is  hoped 
that  study  by  neuropathologists  of  these  brains  with  inflam- 
matory changes  still  fresh  may  solve  some  of  the  unsettled 
problems. 

In  lues,  if  there  is  a  paresis  of  accommodation  there  is  also 
dilatation  of  the  pupil  and  iridoplegia — an  ophthalmoplegia 
interna.  A  peculiarity  of  encephalitis  pupils  is  that  in  many 
cases  there  is  a  paresis  or  even  complete  paralysis  of  accom- 
modation without  dilatation  of  the  pupil — in  other  words 
there  is  a  normal  pupil  or  an  undilated  Argyll-Robertson 
pupil  plus  the  paresis  of  accommodation  that  formerly  we 
saw  as  an  isolated  symptom  in  diphtheria  alone.  This  paresis 
of  accommodation  in  encephalitis,  furthermore,  is  usually 
bilateral,  whereas  in  lues  it  is  mostly  found  in  one  eye  only. 

The  characteristic  features  of  the  sluggish  pupil  found  in 
encephalitis  then  are,  first,  the  great  frequency  of  accompany- 
ing defective  convergence  reaction,  and  second,  the  association 
often  with  paresis  of  accommodation  without  dilatation  of  the 
pupil. 

Accommodation.  Accommodation  may  be  apparently  nor- 
mal by  the  tests,  yet  the  patient  may  not  be  able  to  maintain 
it  for  a  length  of  time,  that  is,  there  is  quick  fatigue  of  accom- 
modation, or  there  may  be  various  degrees  of  actual  loss  of 
accommodation.  When  there  is  actual  loss  of  accommodation 
the  hyperopic  patient,  who  is  accustomed  to  overcome  his 
hyperopia  by  exercising  his  accommodation,  finds  that  his  dis- 
tant vision  has  suffered  as  well  as  his  near  vision.  And  the 
emmetropic  patient  finds  that  he  can  read  print  only  with 
great  effort  and  by  holding  it  at  arm's  length.  This  paresis 
of  accommodation  may  easily  be  overlooked  in  the  bed 
patient,  but  the  ophthalmologist  finds  it  frequently  in  the 
convalescent. 

Facial  Symptoms.  The  facial  palsy  is  for  the  most  part 
slight  and  often  limited  to  the  lower  branches.  It  is  rarely 
sufficiently  pronounced  to  give  rise  to  Iagophthalmos  or  even 
to  cause  difficulty  in  closing  the  eyelids. 


66  ACUTE  EPIDEMIC  ENCEPHALITIS 

Since  the  eye  disturbances  of  encephalitis  are  sometimes 
of  early  onset  and  then  the  most  annoying  of  the  patient's 
symptoms,  the  ophthalmologist  may  be  the  first  physician 
to  be  consulted  and  in  times  of  epidemic  he  may  from  the 
eye  symptoms  alone,  if  lues  can  be  excluded,  make  the 
diagnosis. 

The  following  questions  submitted  to  Dr.  Holden  before 
the  commission,  together  with  answers  to  them,  are  here 
reported  verbatim. 

Dr.  Sachs:  I  would  like  to  ask  Dr.  Holden  whether  he  attaches 
any  importance  at  all  to  the  irregularity  of  pupillary  contour  that 
has  been  observed  in  these  cases.  You  make  a  distinction;  I  believe 
you  stated  that  the  contour  is  irregular  but  with  a  sluggish  pupil, 
just  as  though  you  associated  those  two  things  in  some  way,  or 
are  they  in  any  sense  independent?  . 

Dr.  Holden:  I  think  we  all  feel  that  the  pupil  of  cerebral  lues, 
for  example,  begins  with  irregularity  and  inequality  and  is  followed 
by  a  sluggishness  of  light  reaction.  These  pupils  seem  to  me  to  fol- 
low fairly  well  the  model  of  the  Argyll-Robertson  pupil  in  its 
incipiency.  The  irregularity  in  equality  was  noted  in  but  7  cases 
in  which  there  were  no  sluggish  pupils,  nor  sluggishness  of  light 
reaction. 
!Dr.  Dana:  Was  there  any  case  of  sympathetic  paralysis? 

Dr.  Holden:  I  have  not  found  any  notes  of  these.  There  is  a 
record  of  one  ol  the  Philadelphia  neurologists  who  reported  a  case 
of  what  he  termed  bilateral  sympathetic  paralysis.  In  other  words, 
he  had  the  slight  narrowing  of  the  palpebral  aperture  and  the 
contracted  pupil  which  we  have  as  symptoms  of  the  disturbance 
of  the  cervical  sympathetic,  and  he  regarded  this  as  being  unique 
in  this  disease  as  occurring  on  both  sides;  as  a  rule  it  is  not  ob- 
served. Now,  as  an  ophthalmologist  I  would  rather  question  the 
accuracy  of  his  observation.  I  was  not  at  all  sure  that  his  diagnosis 
was  correct. 

Dr.  Sachs:  I  think  we  have  all  seen  some  of  those  cases  that 
should  probably  have  gone  in  the  first  instance  to  the  oculist. 
Tell  us  something  about  the  length  of  time  which  you  know  that 
the  ocular  palsies  have  persisted  in  these  cases.  Have  they  been 
chronic? 


SYMPTOMATOLOGY  67 

Dr.  Holden:  Many  of  the  cases  that  I  saw  in  my  office,  of 
patients  who  came  with  the  eye  symptoms  first,  were  afterwards 
sent  to  hospitals  and  were  lost  to  my  observation.  I  cannot  answer 
that  question  definitely. 

Dr.  Barker:  Dr.  Holden  has  not  said  much  about  the  fourth 
nerve.  Was  it  involved  in  these  cases,  or  does  it  usually  escape? 

Dr.  Holden:  There  was  no  note  of  the  fourth  nerve  involve- 
ment in  the  Mt.  Sinai  Hospital  cases.  I  have  not  observed  it 
myself.  Naturally,  in  bed  patients,  the  fourth  nerve  involvements 
are  difficult  to  make  out.  I  have  no  doubt  it  has  been  involved 
in  a  good  many  cases,  but  this  does  not  appear  in  the  statistics. 

Dr.  Hall:  Could  the  small  pupil  be  due  to  a  sympathetic 
paralysis?  Small  pupils  are  quite  common  in  encephalitis.  Do  you 
think  it  is  an  irritation  of  the  oculomotor?  Why  is  there  miosis? 

Dr.  Holden:  My  theory  about  all  these  pupils,  the  luetic  pupil 
and  the  others,  is  that  there  is  an  irritation  to  begin  with  which 
causes  an  irregular  contraction  of  the  sphincter  muscle.  First 
we  have  an  irregularity  and  later  a  small  pupil.  I  cannot  see  any 
reason  for  dragging  the  sympathetic  into  these  cases. 

Dr.  Hall:  Dr.  House  of  Oregon  has  spoken  especially  of  weak 
movements  of  both  eyeballs — inability  to  do  much  of  anything 
with  any  of  the  eye  muscles — what  might  be  called  a  sluggish 
eyeball  as  contrasted  with  sluggish  pupils.  What  would  Dr. 
Holden's  idea  be  of  the  lesion  that  could  cause  such  a  phenomenon 
as  that — sluggish  eyeball,  where  all  the  movements  are  paralytic. 

Dr.  Holden:  I  think  it  is  rather  difficult  to  say  except  that  I 
regard  a  certain  number  of  those  cases  as  purely  mental  such  as  we 
have  all  noticed  in  examining  patients  in  the  hospital;  for  instance, 
that  it  is  very  difficult  to  get  almost  any  of  those  patients  to  look 
upward,  and  in  ^these  encephalitis  patients  it  is  very  difficult  to 
get  them  to  look  aside  sometimes.  I  have  to  give  tests  to  be  sure 
that  the  patient  has  not  paralysis.  Of  course,  in  the  cerebellopon- 
tile  angle  tumors  we  find  what  we  may  term  a  disinclination.  The 
patient  requires  a  good  deal  of  urging  to  turn  his  eyes  to  the 
right  in  the  case  of  right  tumor.  It  is  difficult,  I  think,  to  distinguish 
between  the  cases  of  mental  disinclination  and  those  in  which 
there  is  actual  nerve  weakness. 

Dr.  Dana:  Referring  to  the  sympathetic  again,  did  not  Dr. 
Cadwalader  report  other  symptoms  which  belong  to  cervical 
sympathetic  paralysis,  like  sweating  and  reaction  of  the  pupils, 
etc.? 


68  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Holden:  As  I  remember  it,  the  report  was  about  thirty 
lines  long  only,  and  I  do  not  remember  that  he  mentioned  other 
symptoms. 

Dr.  Patrick:  You  spoke  in  rather  a  cursory  way  of  the  possi- 
bility of  various  varieties  of  the  spasm  of  the  ocular  muscles  as  well 
as  the  paralysis.  Might  I  ask  if  you  have  seen  ocular  spasms  in 
these  cases  and  to  what  extent? 

Dr.  Holden:  After  I  had  written  this  paper  I  crossed  out 
"spasm"  and  then  I  put  it  in  again,  because  there  were  some  cases 
reported  of  the  spasm  of  the  orbicularis.  I  think  some  of  these 
cases  might  come  under  the  head  of  "spasm."  I  have  not  seen 
any  other. 

Dr.  Sachs  :  Have  you  seen  what  we  have  described  as  cogwheel 
movements  of  the  eyeballs?  Have  you  been  struck  by  the  jerky 
movement  of  the  eyeball?  We  thought  that  the  expression  "cog- 
wheel" movement  would  about  express  it. 

Dr.  Holden:  I  think  I  have. 

CONCLUSIONS    OF    THE    COMMISSION 

Mode  of  Invasion.  Members  of  the  Commission  are  of  the 
opinion  that  no  dogmatic  statement  can  be  made  at  the 
present  time  as  to  the  exact  mode  of  invasion  of  the  infective 
agent. 

The  suggestion,  therefore,  that  the  mucous  membranes 
are  the  seat  of  primary  involvement,  the  infection  then  ex- 
tending along  the  lymph  paths  must  be  accepted  with  re- 
serve; also  the  statement  that  nerve  palsies  are  related  to  the 
primary  and  original  site  of  infection. 

While  the  importance  of  the  lymphatic  system  in  the 
extension  of  inflammatory  affections  of  the  central  and 
peripheral  nervous  systems  is  now  well  recognized,  the 
blood-stream  is  no  less  important. 

In  any  investigation  of  this  question,  therefore,  the 
hematogenous,  as  well  as  the  lymphogenous,  factors  should 
receive  consideration. 

The  statement  was  also  made  that  the  more  highly  organ- 
ized cells  of  the  central  nervous  system  are  more  subject  to 
the  ravages  of  the  disease. 


SYMPTOMATOLOGY  69 

The  Commission  is  of  the  opinion  that  while  the  general 
principle  may  be  recognized,  that  the  higher  the  degree  of 
organization  of  the  nerve  cell  the  greater  its  vulnerability, 
this  does  not  apply  to  infections  of  the  type  under  considera- 
tion. Here  other  factors  must  be  considered  and  especially 
one  which  is  rather  obscure  at  the  present  time,  namely,  the 
elective  affinity  of  certain  bacteria  or  their  toxins  for  certain 
groups  of  nerve  cells. 

Special  Clinical  Type.  It  has  been  the  custom  in  the 
classification  of  all  general  infections  of  the  central  nervous 
system  to  designate  special  clinical  types  in  relation  to 
anatomical  structures,  e.  g.,  cerebral,  cerebellar,  spinal,  etc. 

Strict  anatomical  divisions  in  general  infections  of  the 
nervous  system  are  always  arbitrary  and  the  type  is  rarely  so 
definite  as  its  name  would  indicate  and  is  often  only  indica- 
tive of  a  predominant  symptomatology. 

This  appears  to  be  true  of  the  so-called  cerebral  and  cere- 
bellar types  of  encephalitis.  These  types  are  not  only  rare,  but 
where  they  do  occur  they  are  associated  with  other  focal 
symptoms  which  blur  the  purity  of  the  clinical  picture. 

In  some  cases  the  cerebellar  symptomatology  is  to  be 
ascribed  to  lesions  involving  the  cerebellar  connections  in  the 
midbrain  rather  than  to  the  cerebellum  itself. 

Basal  Ganglia  Group.  One  of  the  striking  clinical  features 
of  this  disease  has  been  the  involvement  of  the  corpus 
striatum  with  the  development  of  symptomsof  paralysis 
agitans  and  of  chorea  as  pure  clinical  types  or  in  combina- 
tion. The  relationship  of  chorea,  choreo-athetosis,  dystonia, 
and  paralysis  agitans  to  the  corpus  striatum  has  been 
shown  by  a  number  of  studies  in  recent  years.  Their  occur- 
rence in  connection  with  the  predominantly  brain  stem 
involvement  of  epidemic  encephalitis  is  therefore  not 
surprising,  although  practically  unknown  in  other  types  of 
infection  of  the  central  nervous  systems,  as,  for  example, 
epidemic  poliomyelitis.  Of  special  interest  is  the  occurrence 
of  symptoms  of  both  paralysis  agitans  and  chorea,  prac- 
tically in  pure  form,  which  would  appear  to  favor  Ramsay 


7o  ACUTE  EPIDEMIC  ENCEPHALITIS 

Hunt's  conception  of  the  two  striatal  systems, — the  one 
motor,  for  the  control  of  automatic  and  associated  move- 
ments (pallidal  system) ;  and  the  other  exercising  an  inhibi- 
tory and  coordinating  function  (neostriatal  system). 

It  is  to  be  hoped  that  careful  studies  in  the  future,  includ- 
ing serial  sections  of  this  region,  will  throw  additional  light 
on  these  important  questions. 


Chapter  III 

SYMPTOMATOLOGY:  SYMPTOMS  REFERABLE  TO 

THE  SPINAL  CORD  AND  PERIPHERAL 

NERVES 

THIS  portion  of  the  section  on  symptomatology  of  epide- 
mic encephalitis  concerns  the  coincidence  of  this  disease 
in  parts  of  the  central  nervous  system  other  than  the  enceph- 
alon,  and  the  Commission  submits  clinical  and  laboratory 
observations  as  follows:  The  report  of  Dr.  Henry  A.  Riley 
of  New  York,  upon  spinal  types  of  the  disease,  and  the  report 
of  Dr.  Foster  Kennedy  of  New  York,  upon  peripheral  and 
radicular  types.  Also,  the  report  on  laboratory  findings,  of 
Dr.  Walter  M.  Kraus  of  New  York,  and  of  Dr.  Irving  H. 
Pardee  of  New  York,  gives  the  serology  of  the  spinal  fluid 
and  blood  in  epidemic  encephalitis. 

Spinal  Types  of  Epidemic  Encephalitis  (Henry  A. 
Riley).  This  form  was  late  of  recognition  being  considered 
first  as  an  aberrant  form  of  poliomyelitis  associated  with 
somnolence.  Only  the  increasing  number  of  cases  made  it 
evident  that  there  was  a  distinct  form  of  spinal  involvement 
of  epidemic  encephalitis. 

Pure  examples  of  any  one  form  or  type  being  almost 
unknown,  only  the  predominating  picture  determines  the 
label  to  be  applied  to  the  disease. 

Figures  by  Wechsler  show  that  out  of  864  cases,  44  cases 
were  described  as  myoclonic,  29  as  radicular,  neuritic  or 
neurologic,  24  as  meningitic,  and  1  as  dorsal  poliomyelitic, 
a  total  of  121  cases.  On  account  of  the  loose  description  and 
terminology,  only  23  cases  can  be  considered  as  spinal,  these 
being  myelitic,  paraplegic  and  ventral  poliomyelitic. 

71 


72  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  forms  of  epidemic  encephalitis  which  are  apparently 
mainly  spinal  in  character  may  be  divided  into  two  groups: 

i.  The  ventral  poliomyelitic  form. 
2.  The  transverse  myelitic  form. 

The  ventral  poliomyelitic  form  may  be  divided  into  two 
sub-groups : 

a.  The  irritative  type. 

b.  The  paralytic  type. 

Rarely  seen  as  clear-cut  entities,  these  merge  one  into 
another;  the  paralytic  type  is  often  the  end  result  of  the 
irritative.  The  irritative  type  may  clear  up  without  any 
permanent  defect;  the  paralytic  may  develop  full  blown. 

Irritative  Type.  The  literature  is  not  clear  in  definite 
distinguishing  features  in  motor  disturbances,  observations 
being  mixed  and  conflicting.  The  character  of  movement 
is  the  criterion  by  which  the  level  of  the  disturbance  may 
be  identified. 

a.  The  cortical  level  is  distinguished  by  the  movement 
being  a  purposeful  synergized  movement,  presenting 
elements  which  distinguish  not  only  the  cortical  pattern  and 
concept,  but  also  the  collaboration  of  the  cerebellum  in  the 
movement;  for  example,  the  movement  displayed  in  Jackson- 
ian  epilepsy.  The  arrangement  of  the  Betz  cells  and  the 
ventral  horn  cells  makes  the  cortical  type  of  movement  a 
synergized  movement,  and  not  an  aimless  contraction  of 
independent  muscles  or  muscle  fibers.  Such  cortical  stimuli 
are  incapable  of  bringing  about  myoclonic  or  fibrillary 
contractions. 

b.  The  striate  level  is  distinguished  by  the  movements 
which  we  know  as  the  choreas,  the  athetoses  and  the  mobile 
spasms.  The  underlying  feature  being  the  automatic  asso- 
ciated type  of  movement,  we  can  differentiate  these  from 
the  spinal  level  of  motility. 

c.  The  cerebellar  level  need  not  be  considered,  for  we 
do  not  have  any  definite  type  of  abnormal  involuntary 
movement  from  stimulation  of  the  cerebellum. 


SYMPTOMATOLOGY  73 

d.  The  spinal  level  of  movement  characterizes  the  myo- 
clonic and  the  fibrillary  manifestations  of  epidemic  encepha- 
litis. Such  contractions  at  most  produce  a  movement  of 
a  single  muscle,  and  at  their  least  produce  a  movement  of  a 
single  muscle  fasciculus.  They  are  simple  purposeless  irregu- 
lar movements.  The  coarse  myoclonic  movements  are  twitch- 
ing, exceedingly  rapid  in  rate,  irregular  in  rhythm  and 
variable  in  extent.  At  times  slow  vermicular  movements  have 
been  observed,  probably  due  to  the  stimulation  of  connector 
neurons  in  the  spinal  gray  and  the  resulting  correlated 
activity  of  several  neuron  groups.  The  myoclonic  form  was 
often  preceded  for  several  days  by  radicular  pains  and  the 
interval  may  indicate  the  time  necessary  for  the  infective 
agent  to  spread  from  the  roots  to  the  parenchyma  of  the 
cord  itself. 

Paralytic  Type.  The  paralytic  type  of  the  ventral  polio- 
myelitis form,  closely  resembles  that  seen  in  poliomyelitis; 
in  fact,  of  itself  it  is  indistinguishable  from  that  disease.  The 
history  and  concomitant  phenomena  establish  the  differential 
diagnosis. 

The  transverse  myelitic  form  of  epidemic  encephalitis 
is  similar  to  the  transverse  myelitis  seen  in  other  forms 
of  spinal  disease  and  varies  with  the  site  and  extent  of 
the  lesion.  By  some  it  has  been  considered  not  as  a  definite 
type  but  as  an  accidental  occurrence  in  the  course  of  a 
typical  spinal  encephalitis,  the  result  of  hemorrhage  or 
thrombosis.  Occasional  xanthochromia  may  substantiate 
this  view. 

CASE    REPORTS 

Case  I.  An  irritative  type  from  the  service  of  Dr.  Foster 
Kennedy  at  the  Neurological  Institute,  New  York  City. 

Onset  seven  weeks  before  admission,  with  pain  and  soreness 
spreading  from  the  head  to  the  entire  body;  retention  of  urine, 
transient  diplopia,  insomnia  and  tremor. 

Fixity  of  facial  expression;  coarse  tremor  of  upper  and  lower 
extremities,   transient   cogwheel   in   flexing   forearm,   brief  jerky 


74  ACUTE  EPIDEMIC  ENCEPHALITIS 

movements  of  the  toes  and  feet  and  myoclonic  contractions  of 
dorsal  muscle  groups  in  the  thigh.  Abdominal  myoclonus.  Deep 
reflexes  sluggish,  abdominals  absent,  no  pathological  reflexes.  No 
sensory  changes  of  note.  Slight  external  rectus  weakness  on  the 
right  side.  Laboratory  examinations  negative. 

Case  II.     A  myoclonic  fibrillary  type. 

Onset  with  pins  and  needles  sensation,  then  pain  in  left  instep, 
which  was  sharp,  localized  and  stabbing.  This  spread  to  right 
leg,  and  then  subsided  and  was  followed  by  twitching  movements 
in  calves,  thighs  and  abdomen.  Patient  delirious,  hallucinating 
with  expansive  tendencies  for  some  time. 

Could  not  walk  on  heels  or  toes.  Gait  was  steppage.  Cerebellar 
function  normal.  Left  knee-jerk  strong;  right  knee  jerk  weak. 
Ankle  reflexes  absent.  Abdominal  reflexes  present  on  right  and 
doubtful  on  left.  No  pathological  reflexes.  Muscle  strength  dimin- 
ished in  abductors  of  thighs  both  sides.  Adductors  of  thighs,  left, 
affected  more  than  right.  Extension  and  flexion  of  feet  very  weak. 
Atrophy  of  left  thigh  and  calf.  Sensory:  Some  change  over  right 
L5—  S5;  left  L2  — S5.  Right  pupil  larger  than  left  with  normal 
reactions. 

Case  III.  A  transverse  myelitic  form  from  the  service  of  Drs. 
Frederick  Tilney  and  Hubert  S.  Howe  at  the  Presbyterian  Hos- 
pital, New  York  City. 

Onset  with  dizziness,  diplopia,  headache,  left  facial  paralysis. 
Right  ptosis. 

Reflexes  of  upper  extremity,  active;  of  lower  extremity,  absent; 
no  abdominal  or  pathological  reflexes.  No  movement  of  lower 
extremity  except  slight  flexion  and  extension  of  the  toes.  Tone 
much  reduced  in  lower  extremities.  Level  at  T2  —  4  with  secondary 
level  at  S2  for  all  types  of  sensation. 

Slight  papillitis  in  each  eye,  pupils  equal,  regular  and  central, 
both  sluggish  to  light  and  accommodation,  left  more  than  right. 
Right  ptosis,  right  eye  immobile;  left  eye,  deficient  internal  rectus. 
Partial  left  seventh. 

Straw  colored  spinal  fluid,  otherwise  laboratory  examinations 
were  negative. 

Following  lumbar  puncture  the  patient  developed  a  total 
transverse  lesion  at  the  level  of  T2,  complete  paraplegia,  retention 
of  urine,  pneumonia  and  death.  No  autopsy. 


SYMPTOMATOLOGY  75 

The  following  questions  submitted  to  Dr.  Riley  before  the 
Commission,  together  with  the  answers  to  them,  are  here 
reported  verbatim. 

Dr.  Sachs:  I  would  like  to  ask  Dr.  Riley  this  question:  Have 
you  seen  paralytic  spinal  types  which  you  could  at  the  time  diag- 
nose as  due  to  the  virus  of  epidemic  encephalitis  and  not  to  that  of 
acute  poliomyelitis?  I  mean,  if  you  had  not  seen  them  just  at  the 
time  of  the  epidemic,  was  there  anything  about  those  cases  to 
help  you  at  the  time  to  differentiate  between  the  paralytic  type 
of  anterior  poliomyelitis  and  the  type  that  is  due  to  the  epidemic 
encephalitis? 

Dr.  Riley:  I  think  the  drowsiness  and  the  cranial  nerve  systems 
would  be  very  valuable  in  differentiating. 

Dr.  Sachs:  That  is,  nothing  in  the  spinal? 

Dr.  Riley:  I  do  not  think  so. 

Dr.  Timme:  Dr.  Riley,  may  I  ask  whether  you  had  any  reason 
at  any  time  to  believe  that  in  the  ventral  poliomyelitic  type  there 
were  also  involvements  of  the  intermedio  lateral  tract  in  which 
the  sympathetic  cells  were  either  entirely  per  se  involved  or  in 
addition  to  the  anterior  horn  cells? 

Dr.  Riley:  I  do  not  think  I  have  seen  any  cases  that  showed 
that.  Usually  there  was  some  motor  disturbance  in  connection 
with  the  anterior  horn  manifestations,  but  I  have  not  seen  any- 
thing of  that  alone. 

Dr.  Timme:  Would  you  be  willing  to  include  in  your  classifica- 
tion the  addition  of  symptoms  that  would  be  due  to  such  dis- 
turbance of  the  intermedio  lateral  tract? 

Dr.  Riley:  I  think  they  should  be,  but  they  rarely  are  in  the 
ordinary  routine  examination. 

Dr.  Timme:  You  think  they  should  appear?  Should  the  classifica- 
tion include  that? 

Dr.  Riley:  Yes,  I  think  it  should. 

Dr.  Dana:  I  would  like  to  ask  Dr.  Riley  if  he  is  sure  that  that 
last  case  as  reported  is  a  case  of  encephalitis  Iethargica.  I  do  not 
see  how  that  can  be  a  certainty.  It  is  just  with  a  group. 

Dr.  Riley:  The  history  of  some  drowsiness,  and  the  cranial 
nerve  symptoms  which  were  quite  marked  in  that  case, — both 
sides  were  affected,  one  more  so  than  the  other, — and  with  the 
other  spinal  manifestations,  the  case  could  hardly  be  placed 
anywhere  else. 


76  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Dana:  That  is  not  making  a  diagnosis.  How  can  you  ex- 
clude some  sort  of  a  mixed  infection?  It  is  so  entirely  different  in 
its  course  from  perhaps  ioo  cases  of  epidemic  encephalitis. 

Dr.  Riley:  I  think  that  was  just  the  characteristic  thing  about 
the  disease,  as  we  saw  it,  that  it  did  not  follow  any  outline. 

Dr.  Dana:  That  is  just  the  point  I  think  has  been  too  greatly 
emphasized — the  characteristics  of  exceptional  cases.  I  have 
seen  cases  over  and  over  again,  and  they  have  a  physiognomy 
that  is  quite  characteristic  and  distinct.  They  do  not  always  run 
to  these  bizarre  forms.  You  have  them  and  then  immediately  you 
form  a  new  type  without  any  post  mortem  evidence  of  it.  Is 
there  on  record,  for  example,  a  case  like  the  one  you  have  described 
— very  marked  sensory  symptoms  in  which  there  has  been  a  post 
mortem  which  has  shown  that  the  case  was  surely  encephalitis? 

Dr.  Riley  :  There  was  another  case  at  the  Presbyterian  Hospital 
which  was  autopsied  and  showed  a  symmetrical  diminution  in  the 
size  of  the  cord  and  also  hemorrhages  and  destructive  processes 
in  the  midbrain,  etc.  It  seemed  to  be  quite  typical  of  what  we 
recognize  as  epidemic  encephalitis. 

Dr.  Dana  :  I  am  not  saying  that  this  is  not  so,  but  I  am  reading 
a  good  many  of  the  papers  and  listening  to  them,  and  it  always 
seems  as  though  they  were  trying  to  show  another  bizarre  case, 
and  emphasizing  extraordinarily  unusual  types.  Moreover,  I 
don't  think  the  cases  have  always  been  worked  out  so  as  to  exclude 
absolutely  some  other  infection  or  some  mixed  infection  in  those 
cases. 

Dr.  Sachs:  There  is  one  other  point  I  would  like  to  have  some 
information  upon  for  the  benefit  of  the  Commission.  I  may  not 
have  understood  you  correctly,  but  did  you  not  make  a  point 
that  in  spinal  types,  we  will  say,  of  acute  poliomyelitis,  there  were 
never  cases  resembling  a  transverse  myelitis? 

Dr.  Riley:  If  I  did  make  that  positive,  I  ought  to  qualify  it 
somewhat. 

Dr.  Sachs:  I  remember  distinctly,  at  the  time  of  the  epidemic 
of  acute  poliomyelitis,  having  seen  such  cases  which  were  really 
typical  transverse  myelitis.  The  only  evidence  that  we  had  that 
they  were  of  this  nature  was  the  unusually  rapid  recovery,  very 
much  more  rapid  than  in  any  other  diseases  we  had  ever  seen. 
I  should  be  glad  to  know  whether  from  your  study  of  the  litera- 
ture you  found  that  there  was  no  basis  for  the  diagnosis  of  epidemic 


SYMPTOMATOLOGY  77 

poliomyelitis  in  these  cases,  whereas  I  believe  you  say  there  were 
some  in  this  epidemic.  That  is,  I  understood  you  to  claim  that  there 
was  no  reason  to  suppose  that  in  the  epidemic  of  poliomyelitis 
any  cases  of  acute  transverse  myelitis  occurred,  which  could  be 
classified  as  due  to  that  epidemic,  whereas  you  did  think  there 
were  some  such  cases  occurring  during  an  epidemic  of  encephalitis. 

Dr.  Riley:  Yes,  that  is  true.  We  got  that  impression  from  the 
literature  and  also  from  some  ot  these  cases.  For  instance,  this 
last  one  only  developed  a  transverse  myelitis  picture  after  a  lumbar 
puncture,  and  that  is  the  reason  I  said  that  some  had  con- 
sidered the  transverse  myelitis  forms  as  simply  the  result  of  an 
accident  in  the  course  of  epidemic  encephalitis — as  a  hemorrhage 
or  thrombosis,  etc.,  not  as  a  pure  type  of  disease. 

Dr.  Dana:  Then  you  do  say  that  possibly  these  definite  trans- 
verse myelitis  pictures  may  be  accidental? 

Dr.  Riley:  Yes,  I  do  not  know  myself;  I  am  quoting. 

Peripheral  and  Radicular  Types  (Foster  Kennedy). 
It  is  only  for  the  purpose  of  presentation  of  different  clinical 
aspects  of  epidemic  encephalitis  by  different  observers  that 
we  have  divided  with  some  arbitrariness  the  disease  into 
different  clinical  groups.  A  clinical  discussion,  under  these 
circumstances,  therefore,  must  begin  by  a  disclaimer  that  a 
type  is  ever  a  disease  of  its  own  genus,  and  by  an  assertion 
that  it  merely  represents  a  variety  in  which  the  virus  has 
fallen  with  some  greater  incidence  on  one  part  of  the  body 
than  on  another.  Of  the  circumstances  which  go  to  permit 
this  variety  of  form  we  know  little;  naturally,  disease  pic- 
tures will  vary  with  the  structure  affected,  and  variety  in 
such  pictures  following  nervous  lesions  is  furthered,  because 
from  lesions  of  the  nervous  system  we  may  have  either 
obliterations  of  normal  functions  or  release  of  functions  nor- 
mally controlled  by  centers  higher  in  the  neural  hierarchy. 

It  is  probable  that  variety  of  clinical  form  in  epidemic 
encephalitis  is  often  produced  by  variety  of  virus  or  by  a 
constant  virus  varied  by  appearing  in  different  evolutionary 
guises. 

However  this  may  be,  it  is  certain  that  the  peripheral 


78  ACUTE  EPIDEMIC  ENCEPHALITIS 

nerves  and  spinal  roots  are  affected  in  encephalitis  to  a 
considerable  degree. 

Spinal  Root.  Abrahamson  says  that  in  60  per  cent  of  his 
cases  unmistakable  signs  of  radiculitis  were  present.  This  is  a 
higher  figure  than  has  been  obtained  in  the  series  at  Bellevue 
Hospital;  we  have  been  slow,  however,  to  ascribe  to  root  or 
peripheral  infection  subjective  symptoms  unsupported  by 
objective  phenomena.  Nevertheless,  in  some  cases,  the  dis- 
tribution and  character  of  the  pains  have  forced  us  to  the 
same  conclusions;  jn  a  few  others,  sensory  changes  similar 
to  those  found  in  tabes  dorsalis  have  been  present;  in  a  small 
number  there  have  been  localized  atrophies  of  muscles  such 
as  would  occur  from  involvement  of  contiguous  anterior  roots. 

Cranial  Nerve.  Palsies  of  single  cranial  nerves  are  not 
uncommon,  the  seventh  and  third  nerves  being  those 
most  usually  affected.  It  should  be  pointed  out  that  the 
involvement  of  the  seventh  nerve  in  most  of  our  cases  has  not 
been  accompanied  by  any  defect  either  of  the  fifth,  eighth  or 
sixth  nerves,  a  consideration  which  would  exclude  the  possi- 
bility of  the  lesion  being  in  the  pontocerebellar  angle  or  in 
the  nucleus  of  the  facial  nerve  in  the  pons,  and  would  compel 
observers  to  explain  the  facial  palsies  in  these  cases  by  a 
lesion  of  the  seventh  nerve  in  its  parenchyma. 

Peripheral  Nerve.  Not  only  were  single  cranial  nerves 
picked  out  for  damage  by  the  infection,  but  occasionally 
single  peripheral  nerve  trunks  were  involved  in  similar 
fashion.  An  interesting  example  of  this  was  seen  in  a  riveter 
who  in  April  of  this  year  began  suddenly  to  have  sharp 
lancinating  pains  in  the  arms  and  shoulders  accompanied  by 
much  weakness  in  the  upper  extremities.  When  examined, 
some  three  weeks  after  the  beginning  of  these  symptoms  he 
was  found  to  have  a  noticeable  loss  of  power  in  both  serratus 
magnus  muscles,  the  right  scapula  being  winged  on  raising 
the  arm  on  that  side.  The  patient  had  diplopia,  heavy  sweat- 
ing, slowness  of  emotional  initiative  and  a  mask-like  facies 
some  four  weeks  after  the  development  of  his  peripheral 
nerve  symptoms.   It  is  at  least  an  interesting  speculation 


SYMPTOMATOLOGY  79 

whether  this  man's  occupation  as  a  riveter  imposing  reiter- 
ated violent  exertion  of  his  serrati  and  notably  of  the  right 
muscle  could  have  had  any  determining  effect  on  the  inci- 
dence of  the  disease  on  the  long  thoracic  nerve. 

Symptoms.  Several  observers,  notably  Pardee  and  Barker, 
have  described  cases  of  severe  girdling  pains  beginning 
in  the  cervical  region  with  persistent  hiccough  and  de- 
scending to  the  lumbar  region  and  lower  extremities.  None 
of  their  cases  had  any  objective  sensory  losses,  but  all  had 
a  pleocytosis  in  the  spinal  fluid.  It  is  remarkable  that 
herpetic  manifestations  were  not  more  frequent  among  such 
patients;  only  one  of  the  Bellevue  Hospital  group  had  herpes, 
and  that  was  confined  to  the  left  auricle  and  external  audi- 
tory canal  and  was  associated  with  a  complete  left  facial 
palsy  of  a  peripheral  type.  A  geniculate  ganglionitis  was  in 
this  case  the  presumptive  lesion. 

Polyneuritis.  Instances  of  indubitable  polyneuritis  on  an 
encephalitic  basis  are  less  common  in  the  experience  of  the 
workers  in  Bellevue  Hospital  and  the  Neurological  Institute 
than  are  the  radicular  types  or  those  in  which  isolated  nerve 
trunks  such  as  the  facial  are  alone  involved. 

J.  D.  a  watchman,  aged  fifty-three,  formerly  a  coachman,  a  man 
who  had  never  drunk  more  than  an  occasional  glass  of  beer,  in 
August,  1920,  began  to  suffer  from  severe  burning  pains  in  the 
calf  muscles,  with  tingling  in  the  toes  and  progressive  weakness  in 
the  legs.  He  became  unable  to  walk  and  at  the  same  time  had 
severe  headaches  and  felt  very  ill.  He  had  a  constant  pyrexia 
of  about  2°F.  After  two  weeks  the  same  symptoms  as  had  been 
in  the  legs  were  felt  in  the  arms  which  gradually  weakened. 
A  month  after  these  developments  he  began  to  see  double,  his 
pupils  became  unequal  and  sluggish  to  light,  the  left  face  became 
paresed,  the  facial  expression  grew  mask-like,  he  sweated  exces- 
sively; the  sleep  mechanism  was  reversed,  that  is,  he  was  drowsy 
by  day  and  wideawake  by  night,  the  pulse  was  persistently  about 
125,  and  the  sugar  content  of  the  spinal  fluid  and  its  cell  content 
were  greatly  increased.  There  was  atrophy  in  the  intrinsic  muscles 
of  both  hands  and  fibrillary  twitching  in  all  four  limbs.  All  deep 


80  ACUTE  EPIDEMIC  ENCEPHALITIS 

reflexes  were  abolished.  There  was  excruciating  tenderness  in  the 
calf  muscles  and  abolition  of  the  sense  of  position  in  the  feet  and 
hands  with  consequent  sensory  ataxia.  There  was  no  weakness  in 
speech  or  swallowing.  Micturition  was  slow  and  difficult,  but  there 
was  no  incontinence. 

This  man  is  making  a  slow  recovery  (December,  1920). 
This  case  and  two  others  in  the  Neurological  Department  at 
Bellevue  Hospital  remarkably  resembled  those  reported 
before  the  American  Neurological  Association  by  Dr. 
Foster  Kennedy  under  the  caption  "Acute  Infective  Neuro- 
nitis." In  them,  however,  it  was  unusual  to  have  a  cerebral 
symptom  complex,  though  autopsy  examination  revealed 
inflammatory  lesions  in  the  peripheral  nerves,  spinal  ganglia 
and  cord  and  cortex  as  well;  lesions  which  for  the  most 
part,  however,  diminished  as  one  ascended  in  one's  ex- 
amination. 

These  cases  occurred  as  a  minor  epidemic  among  soldiers  in 
the  field  and  were  accompanied  by  fever  and  other  evidences 
of  a  general  infection.  In  some  few  the  posterior  spinal  roots 
were  especially  affected,  so  that  root  zones  of  grossly  altered 
sensibility  were  easily  demonstrated.  A  constant  feature  of 
these  soldiers  was  the  peripheral  paralysis  of  one  or  both 
sides  of  the  face,  a  feature  commonly  but  by  no  means 
constantly  seen  in  the  American  cases  of  epidemic  enceph- 
alitis. 

In  connection  with  these  cases,  however,  we  must  consider 
those  cases  of  acute  polyneuritis  which  occur  as  a  complica- 
tion of  malaria  and  of  enteric  fever  and  scurvy,  and  perhaps 
especially  those  recently  described  by  Farnell  in  which  a 
staphylococcal  gastro-enteritis  was  promptly  followed  by 
acute  polyneuritic  symptoms  with  not  infrequently  fatal 
results.  All  these  diseases  differ  from  similar  conditions 
found  in  the  encephalitic  epidemic  in  degree  rather  than  in 
type,  but  make  manifest  that  disease  pictures  are  sketched 
and  colored  more  by  the  varying  nature  of  the  structures 
attacked  than  t>y  the  specificity  of  the  invading  virus. 


SYMPTOMATOLOGY  81 

The  following  questions  submitted  to  Dr.  Kennedy  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Dana:  Did  you  have  any  radicular  cases,  purely  sensory — 
I  mean  with  intercostal  neuralgia  and  herpes? 

Dr.  Kennedy:  We  had  one  case  I  mentioned  of  herpes  in  which 
the  left  face  was  completely  paralyzed  with  herpes  in  the  external 
canal,  a  very  definite  case  which  I  think  was  no  doubt  a  geniculate 
ganglionitis.  There  have  been  no  other  cases  of  herpes  in  my 
experience.  One  of  the  cases  I  describe  here  had  a  very  definite 
sensory  ataxia  with  loss  of  sense  of  position  in  the  arms.  He  had 
other  cerebral  manifestations  of  encephalitis  Iethargica.  He  had 
diplopia,  mask-like  face,  heavy  sweating,  etc. 

Dr.  Barker:  Is  it  your  impression  that  those  cases  described 
as  infectious  polyneuritis  by  Bradford  and  others  during  the  war 
come  under  this  group? 

Dr.  Kennedy:  I  saw  those  cases,  Dr.  Barker,  and  they  had 
the  appearance  of  it,  but  they  had  no  lethargic  manifestations  at 
all,  none  of  them.  They  had  all  the  evidence  of  a  general  infection, 
but  they  had  no  evidence  of  a  midbrain  infection.  There  was  one 
patient  I  saw  whom  I  have  not  mentioned  in  this  little  abstract — a 
child  who  in  February  of  this  year  came  down  with  vomiting  and 
severe  gastric  pain,  abdominal  pain,  and  a  torticollis;  saw  double 
and  began  to  lose  power  in  the  arms  and  legs,  so  much  so  that  the 
torticollis  was  of  spasmodic  nature.  There  was  complete  loss  ot 
power  in  the  arms  and  legs  in  that  child  and  that  power  fluctuated. 
There  was  complete  loss  sometimes  and  then  tor  three  weeks 
afterwards  there  would  be  a  little  return  of  power  and  then  there 
would  be  another  increase  in  the  abdominal  pain  and  the  power 
was  gone  again.  Both  the  parents  and  the  doctor  told  me  that  it 
came,  as  it  were,  in  waves;  that  almost  every  four  weeks  from 
February  until  now  there  was  a  little  remission,  but  gradually  the 
waves  of  the  involvement  of  loss  ot  power  of  the  child  became  less, 
and  the  child  is  now  considerably  recovering.  The  recovery  between 
each  attack  was  a  little  bit  more  than  the  next  wave  would  put  it 
back,  so  that  now  in  December  the  child  is  able  to  walk  again  and 
has  lost  a  good  deal  of  its  paralysis,  but  not  all.  There  is  a  great 
weakness  of  the  neck  muscles  so  that  the  head  is  thrown  forward; 
the  knee-jerks  are  not  returned  yet;  the  ankle-jerks  are  returned. 


82  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  same  condition  of  rapid  wave-like  attacks  of  the  disease 
was  seen  during  the  war.  I  would  examine  a  soldier  at  eight  o'clock 
one  night  and  find  definitely  that  he  could  not  feel  below  the 
midthigh,  and  I  would  find  twelve  hours  later  that  he  could  feel 
only  below  the  ankle — a  condition  which  I  could  not  understand. 
I  noticed  that  one  of  the  pathologists  suggested  that  the  essential 
lesion  in  some  of  these  cases  was  an  edema,  flooding  the  nerve 
tissue  and  inhibiting  conduction.  The  clinical  manifestations  that 
I  have  seen  in  some  of  the  encephalitis  cases  and  in  those  cases 
to  which  you  refer,  Dr.  Barker,  made  me  believe  that  they  might 
be  explained  by  an  edematous  phenomenon,  and  of  course  one 
would  point  out  in  that  connection  that  sclerosis  very  often  behaves 
in  a  similar  fashion. 

Dr.  Barker:  Might  I  ask  also  if  there  have  been  sensory 
forms  due  to  neuritis  with  spontaneous  pains  as  a  characteristic 
feature  and  taken  by  the  practitioner  at  first  to  be  infectious 
arthritis  or  myositis,  often  referred  to  orthopedists? 

Dr.  Kennedy:  I  have  seen  those  cases,  but  I  do  not  think  I 
have  seen  them  having  that  sad  conclusion. 

Dr.  Weisenburg:  I  would  like  to  ask  if  Dr.  Kennedy  has 
seen  cases  in  which  the  pains  were  limited  to  certain  parts  of  the 
body  only?  For  example,  I  had  one  patient  to  whom  the  pains 
were  limited  to  the  parts  above  the  line  of  umbilicus  and  never 
below. 

Dr.  Kennedy:  We  have  a  patient  in  Bellevue  Hospital  at  present 
whose  pains  are  confined  to  the  arms.  That  woman  became  affected 
in  February  of  this  year  and  she  has  complained  of  pain  ever 
since.  I  can't  find  there  are  any  objective  changes  oddly  enough 
in  all  that  time  in  her  arms,  but  she  complains  of  excruciating, 
burning  pain  down  the  arms  in  the  lower  segment  distribution. 

Dr.  Dana:  How  are  you  going  to  exclude,  as  the  cause  of  these 
so-called  radicular  pains  and  paralyses,  the  conditions  of  the  spinal 
cord  or  of  the  cerebral  tissue  itself?  Why  do  you  say  a  person  has  a 
shoulder  pain  or  facial  pains?  Facial  pain  may  be  ophthalmic  pain, 
may  it  not? 

Dr.  Kennedy:  Facial  pain  might  be  an  irritation  easily  enough 
of  the  nucleus  of  the  fifth  nerve. 

Dr.  Dana:  Is  there  any  way  of  differentiating  between  so-called 
radicular  pains  and  paralyses  and  edematous  conditions  of  the 
anterior  or  posterior  horns  of  the  spinal  cord? 


SYMPTOMATOLOGY  83 

Dr.  Kennedy:  No,  sir,  I  do  not  think  so.  There  is  evidence  that 
hemorrhages  have  been  found  in  the  posterior  ganglia  in  some 
cases.  That  being  so  one  argues  that  certain  other  clinical  cases 
which  correspond  to  them  in  type  may  have  some  of  the  lesions. 

Dr.  Patrick:  You  spoke  of  a  case  ot  hiccough.  I  should  like 
to  inquire  whether  you  know  that  that  was  a  real  hiccough — 
or  a  spasm  of  the  abdominal  muscles?  I  believe,  Dr.  Kennedy,  you 
quoted  that  from  someone  else. 

Dr.   Kennedy:  That  is  Dr.   Barker's  case. 

Dr.  Sachs:  Has  anyone  as  yet  seen  the  cases  of  hiccough  that 
are  reported  as  being  connected  with  epidemic  encephalitis? 

Dr.  Timme:  We  will  ask  Dr.  Barker  to  answer. 

Dr.  Barker:  Let  me  say  that  I  have  seen  2  cases  of  hiccough, 
described  by  the  practitioners,  lasting  a  long  time,  and  they  seemed 
to  be  definitely  those  of  epidemic  encephalitis.  Several  epidemics 
of  hiccough  were  reported  as  occurring  at  the  same  time  as  the 
epidemic  of  encephalitis.  One  such  case  was  examined  roentgen- 
oscopically,  and  there  was  no  movement  in  that  case  other  than 
contractions  of  the  abdominal  muscles.  That  was  an  abdominal 
muscle  hiccough  rather  than  diaphragmatic,  but  that  is  the  only 
case  I  know  of  trying  to  differentiate.  I  rather  think  these  hic- 
coughs are  associated  with  the  epidemic. 

Dr.  Timme:  Perhaps  Dr.  Hunt  could  answer  something  from 
his  observations  in  his  myoclonic  types  involving  abdominal 
muscles — whether  that  is  an  intensive  type  of  this  form. 

Dr.  Hunt:  In  none  of  my  cases  was  there  anything  that  simu- 
lated a  hiccough.  It  would  have  been  very  defective  observation 
that  would  have  interpreted  any  of  the  movements  as  related  to 
hiccough,  but  I  could  imagine  that  with  a  very  rapid,  definite, 
rhythmical  movement  of  the  upper  abdomen  it  might  simulate 
the  real  hiccough,  but  that  was  not  so  in  my  cases. 

The  Serology  of  the  Spinal  Fluid  and  Blood  in 
Epidemic  Encephalitis*  (Walter  M.  Kraus  and  Irving 

*  The  material  for  this  article  was  obtained  from  records  of  certain  New 
York  Hospitals:  Bellevue,  Mt.  Sinai,  The  Neurological  Institute,  New  York, 
Presbyterian,  Roosevelt  and  St.  Luke's,  and  from  the  following  physicians: 
James  B.  Ayer,  Boston;  Lewellys  F.  Barker,  Baltimore;  Peter  Bassoe,  Chicago; 
Josephine  B.  Neal,  New  York;  Harry  C.  Solomon,  Boston;  Walter  F.  Schaller, 
San  Francisco;  E.  W.  Taylor,  Boston,  and  Lloyd  J.  Thompson,  Boston. 


84  ACUTE  EPIDEMIC  ENCEPHALITIS 

H.  Pardee).  The  subject  matter  which  we  present  has, 
for  the  sake  of  clearness,  been  divided  into  three  parts;  the 
first  contains  a  review  of  the  literature,  the  second  data, 
based  on  the  245  case  reports  obtained  from  the  foregoing 
sources,  and  the  third,  a  section  devoted  to  differential 
diagnosis  by  means  of  the  blood  and  spinal  fluid  serology. 
Review  of  the  Literature.  Until  the  publication,  in  191 7,  of 
the  description  of  the  first  cases  of  epidemic  encephalitis  in 
Vienna,  no  reliable  statistics  of  the  changes  in  the  blood  and 
spinal  fluid  in  this  disease  were  obtainable.  At  this  time,  von 
Economo1  gave  an  account  of  the  clinical  and  laboratory 
findings  which  we  shall  consider  the  first  accurate  data  on 
the  subject.  He  pointed  out  the  following  changes  in  the 
spinal  fluid:  An  excess  of  globulin  was  found  and  the  spinal 
fluid  cell  counts  ranged  from  normal  to  43.  The  fluid  was 
clear  and,  in  some  cases,  under  pressure.  The  only  group  of 
observations  which  were  not  mentioned  by  von  Economo 
concerned  changes  in  the  quantity  of  sugar  in  the  spinal  fluid. 
His  observations  on  the  colloidal  gold  curve  were  summed  up 
in  a  sentence.  No  curves  were  given.  In  this  country,  curves 
were  first  published  by  Josephine  B.  Neal2  in  September, 
19 19.  She  mentioned  the  abnormal  changes  and  the  similarity 
to  those  curves  found  in  acute  anterior  poliomyelitis.  Follow- 
ing this,  observations  on  the  occurrence  of  syphilitic  and 
paretic  types  of  curves  were  made  by  Bassoe,3  Brill  and 
Benson,4  Davis  and  Kraus,5  and  Archambault.6 

1  Von  Economo.  Encephalitic  Iethargica.  Wien.  klin.  Wchnschr.,  1917, 
xxx,  581. 

2  Neal,  Josephine  B.  Lethargic  encephalitis.  Arch.  Neurol.  ey  Psychiat., 
September,  19 19,  ii,  271. 

3  Bassoe,  P.  Epidemic  encephalitis  (Nona).  J.  Am.  M.  Assn.,  April  5,  1919, 
Ixii,  971. 

4  Brill  and  Benson.  Lange  reaction  in  epidemic  encephalitis.  J.  Lab.  &° 
Clin.  Med.,  June  20,  1920,  v,  113. 

5  Davis  and  Kraus.  The  colloidal  gold  curve  in  epidemic  encephalitis. 
Am.  J.  M.  Sc.,  1 92 1,  clxi,  109. 

6  Archambault,  La  Salle.  Choreo-athetoid  and  choreopsychotic  syndromes 
as  clinical  types  or  sequelae  of  epidemic  encephalitis.  Arch.  Neurol.  &  Psychiat., 
November,  1920,  iv,  484. 


SYMPTOMATOLOGY  85 

The  foregoing  gives  an  idea  of  the  chronological  order  of 
the  description  of  the  spinal  fluid  findings.  The  following 
paragraphs  will  be  devoted  to  a  detailed  account  of  the  spinal 
fluid  and  blood  findings  given  in  the  literature. 

A.  Spinal  Fluid:  Appearance.  In  the  greatest  majority 
of  cases,  observation  records  a  clear,  colorless  fluid.  Bloody 
fluids  have  occasionally  been  found,  in  fact  more  commonly 
than  could  be  accounted  for  by  the  puncture  of  a  vein.  A 
xanthochromiac  appearance  has  been  extremely  rare. 

Pressure.  The  pressure  of  the  spinal  fluid  varies  from 
normal  to  a  considerable  increase. 

Cell  Counts.  In  spite  of  the  fact  that  von  Economo  in  his 
original  description  made  note  of  a  pleocytosis,  the  French, 
who  had  studied  the  matter  carefully  during  the  years  19 18- 
1919,  had  come  to  the  conclusion  that  a  normal  cell  count 
was  a  rule  and  of  diagnostic  importance.  It  was  not  until 
December  10,  19 19,  when  Benard1  reported  a  case  with 
pleocytosis,  that  doubt  was  thrown  on  the  invariability  of 
normal  spinal  fluid  cellular  content  in  epidemic  encephalitis. 
The  absence  of  pleocytosis  before  this  date,  as  noted  by  the 
French,  was  not  found  by  the  British  and  American  ob- 
servers. The  latter  published  cases  seen  in  19 19,  in  which 
there  appeared  more  than  the  normal  number  of  cells.  The 
cells  which  appeared  in  the  spinal  fluid  were  always  predomi- 
nantly of  the  mononuclear  type  although  polymorpho- 
nuclear increase  up  to  15  per  cent  had  been  found  in  many 
cases. 

The  impression  gathered  from  the  literature  is  that  the 
number  of  cells  may  vary  from  normal  to  an  increase  of 
several  hundred. 

Globulin.  The  discrepancy  between  the  report  of  the 
French,  who  noted  an  absence  of  globulin  in  the  early  cases 
of  the  epidemic,  and  the  English  and  Americans  who  had 

1  Benard,  R.  Le  Iiquide  cephalo-rachidien  dans  I'encephalite  Iethargique. 
Paris  med.,  June  5,  1920,  x,  474.  (This  article  contains  a  thorough  review 
of  the  French  literature  up  to  June,  1920.  References  from  the  literature  of 
other  countries  are  also  given.) 


86  ACUTE  EPIDEMIC  ENCEPHALITIS 

reported  its  presence  in  increased  amounts,  is  a  parallel  to 
the  reports  on  the  cell  counts.  In  general,  it  may  be  said  that 
an  increase   in   globulin   occurs   in  the   majority   of  cases. 

Sugar.  No  report  of  the  amount  of  this  substance  was 
made  until  the  end  of  1919.  From  that  time  until  the  present, 
the  French  have  published  fifteen  observations  on  the 
amount  of  this  substance  in  the  spinal  fluid.  These  varied 
from  0.067  per  cent  to  0.106  per  cent,  averaging  0.085  per 
cent.  It  would  seem,  therefore,  that  the  amount  of  sugar  in 
the  spinal  fluid,  wherever  it  has  been  reported,  has  exceeded 
the  normal  quantity. 

Wassermann  Reaction.  This  has  been  found  negative  in 
the  spinal  fluid  whenever  it  has  been  reported  except  in 
syphilitic  cases. 

Colloidal  Gold  Reaction.  Von  Economo  commented  briefly 
on  the  reaction  of  colloidal  gold  solutions  as  follows:  "The 
gold-solution  reaction  shows  no  typical  elevation  of  its 
curves."  This  implies  that  some  changes  existed. 

B.  Blood:  The  white  blood  counts,  as  reported  in  the 
literature,  reveal  a  variation  from  3,000  to  25,000,  the  average 
being  about  15,000.  Slight  polymorphonuclear  increase  is  the 
rule.  The  remainder  of  the  blood  picture  is  normal.  Obser- 
vations on  the  blood  chemistry  have  been  scattered  and  incom- 
plete. The  blood  Wassermann  reaction  is  reported  negative. 

THE    EVIDENCE    OF    CASE    REPORTS 

The  general  statistics  in  Table  I  give  a  numerical  summing 
up  of  the  case  reports  on  which  we  base  our  data. 

Table  I. — numerical  summing  up  of  case  reports 

Number  of  cases 245 

Number  of  spinal  fluid  cell  counts 260 

Number  of  spinal  fluid  globulin  determinations.    214 

Number  of  spinal  fluid  sugar  determinations 12 

Number  of  spinal  fluid  colloidal  gold  curves 120 

Number  of  spinal  fluid  Wassermann  tests 185 

Number  of  blood  Wassermann  tests 161 

Number  of  blood  polymorphonuclear  counts 171 

Number  of  blood  differential  counts 153 


SYMPTOMATOLOGY 


87 


A.  Spinal  Fluid:  As  a  rule,  the  spinal  fluid  shows  con- 
siderable and  important  changes  in  epidemic  encephalitis. 
These  are  extremely  variable,  not  only  in  different  cases, 
but  also  in  the  course  of  each  case.  The  most  characteristic 
changes  are: 

1.  A  clear,  colorless  fluid. 

2.  An  increase  in  the  pressure  of  the  cerebrospinal  fluid 
when  withdrawn. 


Fig.  6.     Variation  in  the  number  of  cells  in  the  spinal  fluid. 

3.  An    increase    in    the    number    of    mononuclear    cells. 

4.  An  increase  in  the  amount  of  globulin. 

5.  An  increased  amount  of  spinal  fluid  sugar. 

6.  A  negative  Wassermann  reaction. 

7.  The  presence  of  bodies  producing  a  change  in  the  color 
of  a  solution  of  colloidal  gold  (Lange  reaction). 


88  ACUTE  EPIDEMIC  ENCEPHALITIS 

i.  Appearance.  The  fluid  is,  in  most  cases,  clear  and 
colorless.  Occasionally  bloody  fluid  is  obtained. 

2.  The  Pressure.  As  would  be  expected,  the  pressure  of 
the  spinal  fluid  is  sometimes  very  much  increased.  Here  also 
no  rule  exists,  and,  though  this  hypertension  is  frequent,  it  is 
not  universal. 

3.  The  Cell  Count.  Table  II  indicates  the  minimum, 
maximum  and  average  number  of  cells  during  each  of  the  first 

Table  II. — number  of  cells  in  the  spinal  fluid 


Weeks 

Minimum 

AVEEAGE 

Maximum' 

Cases 

I 

2.0 

633 

160.O 

20 

2 

0.0 

71.0 

540.0 

71 

3 

0.0 

373 

200.0 

38 

4 

0.0 

28.2 

222.0 

44 

5 

1.0 

21.3 

70.0 

24 

6 

0.0 

25.7 

100. 0 

26 

7 

1.0 

21  .0 

101  .0 

\2 

8 

2.0 

l6.2 

48.O 

10 

9 

0.0 

13.0 

32.0 

4 

10 

5.0 

8.0 

14.0 

3 

11 

4.0 

40.0 

40.0 

1 

12 

2.0 

15.2 

33-0 

7 

Months 

4 

4.0 

40.2 

108.0 

9 

5 

6 

3-0 

32.0 

6l.O 

2 

7 

2.0 

1 

8 

2.0 

2.5 

3.0 

2 

9 

10 

11 

\2 

13 

21 

.  .  . 

2.0 

1 

24 

.  .  . 

30 

1 

S  YM  PTOMATOLOGY 


89 


Table  III — A.    number  of  cells  in  the  spinal  fluids  at  various  weeks 

INCLUDING  REPETITION   OF   CELL   COUNTS* 


4 

IOO 

70 

IOO 

5 

3 

40 

50 


70 
g 


160 

90 

160 

64 

2 

5 

2 1 

38 

28 

20 

15 

5 

8 

10 

8 

9 
I  I 

I180I 
1350  J 

45 

25 

10 

18 

32 

26 

100 

40 

40 

120 

(.30  1 
I  540  1 

26 

'50 

r50 

270 
1  >5  I 

25 

149 

. 

I  22   1 

16 

18 

IS) 

1  16 

U3 

37 

7 

44 

2 

I  2 

46 

6 

ISO 

200 

4 

6 

20 

20 

122 

2S 

27 

29 

/      30 

1    IOO 

30 
30 

43 

45 

50 

/     54 

1  160 

56 

70 

7  1 

72 

80 

103 

190 

2  (0 

200 

270 

6S0 


114 
18 
18 
20 
SO 
31 
4& 

(50 
I  75 
60 
104 
134 

170 


s 

43 


19 
36 


0 

r 

0 

3 

3 

6 

30 

6 

6 

30 

1  4°  1 

6 

1  42  1 

6 

46  f 

6 

I  57  1 

7 

1  8  ( 

1 
4 

1  11  1 

97 

•     33 

(  8  * 

4 

48 

14 

14 

i  IS  1 

5 

9 

8 

0 

9 

9 

0 

3 

5 

|  10  ) 

IS 

0 

22 

14 

66 

16 

0 

30 

48     32 

1  78  1 

16 
21 

l"l 

1 

1 1 

r 

IS 

28 
40 

1  12  1 
4 

3 
1  1 
28 

10 

5 

18 

24 

5 

25 

7 
13 

30 
101 

30 

S 

No  observation 

28 

30 

IOO 

30 

35 

40  (   2  1 

35 

6 

40 

» 

66 

18 

95 

222 

*  Except  where  repetitions  occur,  the  figures  are  arranged  in  an  ascending  order.  Brack- 
eted figures  indicate  several  observations  on  the  same  case  and  in  the  same  week. 


9o  ACUTE  EPIDEMIC  ENCEPHALITIS 

Table  III — B.  number  of  cells  in  the  spinal  fluids  at  various  months  including 

REPETITION   OF   CELL  COUNTS* 

Months 


24 


4 

/3 

^5   [ 

3 

6 

61 

7 

l9j 

10 

5 

14 

5 

is 

8 

98 

22 

100 

108 

*  Except  where  repetitions  occur,  the  figures  are  arranged  in  an  ascending  order.  Bracketed 
figures  indicate  several  observations  on  the  same  case  and  in  the  same  week. 

twelve  weeks  and  during  the  fourth  to  twenty-fourth  months 
of  the  disease.  The  graph  in  Fig.  6  presents  this  in  a 
different  way.  It  may  be  seen  that,  on  the  average,  more  cells 
are  found  during  the  first  three  weeks  of  the  disease.  The 
value  of  this  in  individual  cases  is  diminished  by  the  varia- 
tions in  the  number  of  cells  in  each  week.  An  idea  of  this  may 
be  had  from  an  examination  of  the  columns  showing  maxi- 
mum and  minimum  number  of  cells  for  each  week  and  also 
from  Table  III.  The  number  of  polymorphonuclear  cells  may 
be  as  great  as  15  per  cent. 

Fluctuation  in  the  number  of  cells  occurs  during  the  course 
of  the  disease.  When  there  is  a  remission,  the  cell  counts  may 
increase. 

4.  Globulin.  The  globulin  is  usually  increased  to  a  mod- 
erate degree  (in  72  per  cent,  of  the  cases).  However,  since 
this  is  not  always  true,  its  diagnostic  value  in  individual 
cases  is  lessened.  The  presence  of  globulin  is  not  always 
paralleled  by  the  presence  of  cells  or  a  positive  colloidal 
gold  curve. 

5.  The  Sugar  Test.  The  majority  of  the  tests  have  been 
done  at  Bellevue  Hospital  since  May,  1920.  No  estimates 
were  given  in  case  reports  outside  of  New  York. 

The  number  of  estimations  is  insufficient  to  enable  us  to 
draw  any  but  tentative  conclusions.  However,  those  figures 
which  we  have,  show,  without  exception,  values  above 
normal. 


S  YM  PTOM  ATOLOG  Y 


9i 


The  sugar  content  of  the  spinal  fluid  has  been  tested  in 
12  cases.  It  has  ranged  from  0.062  per  cent  to  0.095  per 
cent  (Table  IV). 

Table  IV 
Sugar  Content  of  Spinal  Fluid  in  Twelve  Cases 


Mon 


Week 

3 
3 
6 

9 
9 

4 

4 

4 

4 

5 

5 
10 

*  Observations  on  the  same  case. 


Percentage  of  Sugar  in  the 
Cerebrospinal  Fluid 

0.  082 

O.O75 
0.068 
O.062 
O.O94 
O.065 
O.080 
O.O94 

0 . 092  * 

0.070* 

O.063 

O.O95 


6.  The  Wassermann  Test.  This  was  negative  when 
reported. 

7.  The  Colloidal  Gold  Curve.  This  has  been  found  changed 
in  100  out  of  120  cases  (83  per  cent).  The  type  of  curve 
varies  considerably,  as  Figure  7  shows.  There  is  a  tendency 
toward  elevation  of  the  left-hand  part  of  the  curves  in  the 
later  stages  of  the  disease,  but  this  is  not  constant.  Positive 
curves  were  found  as  late  as  the  twenty-first  month.  Eleva- 
tions of  the  right  end  of  the  curve  alone  were  not  found. 

The  tendency  is  to  a  color  change  in  the  high  and  medium 
concentrations  of  spinal  fluid.  Changes  in  the  low  concentra- 
tions do  not  occur  alone,  but  may  occur  when  the  medium 
and  the  high  concentrations  are  altered. 

B.  Blood:  Normal  values  for  red  blood  count  and  hemo- 
globin have  invariably  been  found.  Leukocyte  counts  have 
varied  from  a  minimum  of  4,500  to  a  maximum  of  32,000, 


Q2 


ACUTE  EPIDEMIC  ENCEPHALITIS 


the   general   average   being    12,000.    Figure   8  shows  these 
relations  in  graphic  form. 

Maximum,  minimum  and  average  percentage  of  polymor- 
phonuclears are  shown  in  the  graph  in  Figure  9.  This  will 


J 

* 

4 

* 

^ 

4 

*. 

va 

'^ 

4 

^ 

A 

* 
5a 

4 

HI 

A 

H 

4\ 

A 

H 

}A  i  I 

-£ 

4 

4 

Jk 

*4i  «  J 

14 

Curves 

j  1 

U 

1         *      J 

0                              ■ 

00  i 

A 

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v|           ^       4 

it 

& 

J  4 

j  ■* 

H  H 

fe     1      -6- 

4  * 

^ 

N 

«  ^  ^ 

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A 

4 

4 

H 

4 

4 

1  1   1  1   H=l~ 

4 

^ 

4 

1 

0) 

v 

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< 

- 

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d       CO 

1              c 
A           * 

4m 

1 

4 

1 

< 

1     < 

^ 

4 

I     4    A 

1        4 

5 

ex             1            1 

^ 

4 

I    4    + 

1 

i 

4 

4 

4     < 

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A      t 

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J      4 

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serve   to   emphasize   the   extent   of  the   variations   in   the 
various  stages  of  the  disease. 

The  number  of  observations  on  the  chemistry  of  the  blood 
are  too  few  to  enable  us  to  draw  any  conclusions. 


SYMPTOMATOLOGY 


93 


Weeks/     X     3 
Max 


Auev. 


liui 


No.of 
Cases  /3     6/    24  2f    /3    /£"    f     £     &      /      O    ^ 


Fig. 

8.     Variation  in  leukocyte  counts  in  the  blood. 

Weeks  / 

Z    3     4-    <r    6    7    8    f    A3 

MojL 

Aw 

/    ir* 

'        %7o 

Ave*: 
Mm.. 

j  U 

±So 

Naof 

¥0 

Cases        // 

S6  2/  zi  a  /<?    7   3    z    / 

0    / 

Fig.  (j.     Variation  in  numbers  of  polymorphonuclears  in  the  blood. 


94 


ACUTE  EPIDEMIC  ENCEPHALITIS 


A  few  observations  (12)  on  the  amount  of  sugar  in  the 
blood  have  been  recorded  and  are  within  normal  limits. 
They  are  recorded  in  Table  V. 

Table  V 
Percentage  of  Sugar  in  the  Blood  in  Twelve  Cases 


Week  Month 

2 
2 

3 
3 
3 

3 

4 


4 

5 
6 

7 

*  Observations  on  the  same  case. 


Percentage  of  Sugar  in 
the  Blood 

O.O95 

o .  075 
o.  100 
o.  100 
O.  Ill 

0.083 

O.  120 
o.  100 


o.  no 
0. 170 

0.143 

0.  101 


* 


* 


Wassermann  Reaction.  The  Wassermann  reaction  has 
been  found  negative  when  reported. 

Differential  Diagnosis.  1.  Other  forms  of  meningitis: 
(a)  serous;  (6)  acute  purulent;  (c)  tuberculous;  (d)  syphilitic 
meningitis  and  neurosyphilis. 

2.  Acute  anterior  poliomyelitis. 

3.  Brain  tumor. 

4.  Parkinson's  syndromes  and  allied  conditions. 

5.  Multiple  sclerosis. 

6.  Polyneuritis. 

In  order  to  use  the  serology  of  the  spinal  fluid  in  epidemic 
encephalitis  for  the  purpose  of  differential  diagnosis,  it  is 
necessary  to  make  observations  on  the  pressure,  the  cell 
count,  the  globulin,  the  presence  of  sugar,  the  colloidal  gold 


SYMPTOMATOLOGY  9i 

curve  and  the  Wassermann  reaction.  When  these  observa- 
tions give  no  conclusive  evidence,  a  quantitative  estimate 
of  the  sugar  of  the  spinal  fluid  should  be  made. 

The  various  examinations  mentioned  above  will,  in  the 
majority  of  instances,  serve  to  differentiate  epidemic  encepha- 
litis from  other  diseases  clinically  similar.  Certain  diseases, 
as  will  be  emphasized  in  the  following  paragraphs,  cannot  be 
differentiated  by  all  of  these  means. 

i.  Meningitis:  (a)  Serous  Type  (Meningismus) .  The 
cells  and  globulin  in  this  disease  show  no  deviation  from  the 
normal,  but  the  pressure  is  always  increased.  These  facts 
do  not  serve  as  a  differential  point  for  there  are  some  cases 
of  encephalitis  in  which  the  picture  is  the  same. 

(6)  Acute  Purulent  Meningitis.  In  the  early  stages,  the 
marked  polymorphonuclear  increase  is  the  most  important 
differential  point.  In  the  later  stages,  the  presence  of  cloudy 
opalescent  fluid,  with  cellular  increase  of  several  thousand 
cells,  predominantly  of  the  polymorphonuclear  type,  present 
a  picture  which  is  never  found  in  epidemic  encephalitis. 
The  quantitative  sugar  is  usually  decreased  or  absent,  and 
the  colloidal  gold  solution  may  show  a  color  change  in  the 
higher  dilutions  (right  end  of  the  curve).  Bacteriologic 
examination  may   reveal  organisms  by  smear  or  culture. 

(c)  Tuberculous  Meningitis.  Examination  of  the  spinal 
fluid,  as  thoroughly  as  has  been  suggested  in  the  opening 
paragraphs,  must  be  made  in  order  to  differentiate  this 
disease  serologically  from  epidemic  encephalitis.  It  is  em- 
phasized in  the  literature  that  in  tuberculous  meningitis 
the  cell  count  has  a  tendency  to  increase  during  the  progress 
of  the  disease,  while  in  epidemic  encephalitis  this  is  not  the 
case.  This  observation,  in  our  opinion,  is  of  considerable 
importance,  but  we  do  not  believe  it  to  be  invariably  correct 
since  there  are  cases  of  epidemic  encephalitis  in  the  course 
of  which  the  cell  count  rises  (Table  III).  The  picture  of  the 
spinal  fluid  in  epidemic  encephalitis  may  be  identical  with 
that  of  tuberculous  meningitis  with  one  important  excep- 


96  ACUTE  EPIDEMIC  ENCEPHALITIS 

tion — the  quantitative  sugar.  This  is  almost  invariably 
diminished  in  the  latter  disease. 

The  colloidal  gold  curves  seen  in  tuberculous  meningitis 
are  similar  to  those  found  in  epidemic  encephalitis,  with  the 
possible  exception  of  paretic  types  of  curves.  No  observations 
on  the  presence  of  these  in  tuberculous  meningitis  have 
been  found.  They  are  fairly  common  in  cases  of  epidemic 
encephalitis. 

(d)  Neurosyphilis  and  Syphilitic  Meningitis.  Epidemic 
encephalitis  may  be  ruled  out  by  a  positive  Wassermann 
reaction  in  the  blood  or  spinal  fluid,  except  in  the  rare 
coincidences  of  the  two  diseases.  In  such  cases  no  differ- 
entiating point  can  be  made.  In  cases  in  which  the  Wasser- 
mann reaction  is  not  positive  in  the  spinal  fluid  the  other 
findings  are  of  no  value  when  the  history  or  clinical  findings 
are  clearly  indicative  of  syphilis. 

2.  Poliomyelitis.  This  disease  presents  a  picture  which 
cannot  be  differentiated  (at  the  present  state  of  our  knowl- 
edge) from  epidemic  encephalitis,  in  so  far  as  the  spinal  fluid 
is  concerned.  Further  researches  on  immunologic  tests  and 
quantitative  sugar  estimation  on  the  spinal  fluid  may  yield 
data  of  differential  diagnostic  importance. 

3.  Brain  Tumor.  The  presence  of  a  high  cell  count  is  of 
extreme  rarity  in  brain  tumor;  other  than  this  there  are  no 
differential  points  in  the  diagnosis  from  epidemic  enceph- 
alitis, in  so  far  as  the  spinal  fluid  is  concerned.  In  brain 
abscess,  a  mild  pleocytosis,  usually  of  polymorphonuclear 
cells,  is  often  found. 

4.  Parkinsonian  and  Allied  Conditions.  Since  the  occur- 
rence of  the  recent  epidemic  of  encephalitis,  this  group  must 
be  divided  into  two  parts:  those  caused  by  encephalitis  and 
those  not  caused  by  this  disease.  In  the  acute  and  chronic 
stages  of  both  of  these  groups,  the  spinal  fluid  findings  are  of 
great  differential  diagnostic  importance.  When  the  condition 
is  due  to  encephalitis,  several  or  all  of  the  findings  described 
in  the  foregoing  may  be  found.  When  in  this  group  a  posi- 
tive Wassermann  reaction  is  found,  the  history  of  the  case 


SYMPTOMATOLOGY  97 

will  decide  the  diagnosis  rather  than  the  spinal  fluid  findings, 
and  the  probability  is  that  the  case  is  due  to  syphilis.  The 
Parkinsonian  syndrome  may  be  on  a  syphilitic  basis.  When 
the  condition  is  not  due  to  encephalitis  or  syphilis,  the  spinal 
fluid  is  negative. 

5.  Multiple  Sclerosis.  The  differential  diagnosis  between 
this  disease  and  epidemic  encephalitis  is,  in  our  opinion,  as 
far  as  the  spinal  fluid  is  concerned,  not  possible. 

6.  Polyneuritis.  As  there  are  no  changes  in  the  serology  of 
the  fluid  in  polyneuritis,  while  in  most  cases  of  epidemic 
encephalitis  some  change  is  found,  this  fact  will  serve  as  a 
differential  point. 

Conclusions.  The  spinal  fluid  findings  in  epidemic  enceph- 
alitis have  led  us  to  certain  general  conclusions  in  regard  to 
the  nature  of  the  disease. 

The  course  of  the  disease,  as  illustrated  by  the  serology  of 
the  spinal  fluid,  is  extremely  variable.  A  mild  insidious  or 
chronic  type  lasting  for  months  exists,  as  is  shown  by  the 
continuation  of  abnormal  changes  in  the  spinal  fluid  over 
long  periods  of  time.  An  acute,  fulminating  type  also  exists 
and  may  or  may  not  show  serologic  changes  in  the  spinal  fluid. 
Midway  between  these  two  extreme  types  of  the  disease  is  a 
combination  of  the  acute,  fulminating  and  chronic  insidious 
types.  In  this  type  the  spinal  fluid  findings  indicate  an 
active  process  which,  after  several  weeks,  subsides,  leaving 
few  or  no  serologic  changes.  Then  the  process  lights  up  again 
with  recrudescence  of  abnormal  fluid  findings,  and  may  then 
continue  to  a  fatal  ending  or  what  appears  to  be  a  recovery. 
It  is  striking  that  patients  who  have  died  have  not,  as  a  rule, 
shown  any  marked  aggravation  of  the  spinal  fluid  changes 
before  death.  The  reason  is  that  death  occurs  from  an  in- 
volvement of  vital  centers,  which  is  not  dependent  upon  a 
meningitis. 

The  low  average  of  cell  counts  found  in  this  disease  indi- 
cates that  the  meninges  are  very  little  involved  in  the  patho- 
logic processes,  the  point  of  attack  of  the  infection  being 


98  ACUTE  EPIDEMIC  ENCEPHALITIS 

predominatingly  through  the  vascular  and  lymphatic 
systems.  The  meninges  are  not  directly  attacked. 

The  increase  in  the  spinal  fluid  sugar,  which  has  been  noted 
whenever  tests  of  this  kind  have  been  made,  has  appeared  to 
us  to  be  of  great  interest.  This  has  been  attributed  to  an 
involvement  of  the  center  of  Claude  Bernard  in  the  floor 
of  the  fourth  ventricle.  However,  it  has  also  been  shown  by 
Aschner1  that  "puncture  of  the  floor  of  the  third  ventricle 
causes  intense  glycosuria."  This  arouses  doubt  in  our  minds 
as  to  the  validity  of  the  hypothesis  that  the  hyperglycor- 
rhagia  is  necessarily  due  to  a  lesion  of  the  fourth  ventricle. 

Furthermore,  we  have  been  impressed  by  the  lack  of 
correspondence  between  the  amount  of  spinal  fluid  sugar, 
which  is  always  increased,  and  the  amount  of  blood  sugar, 
which  is  never  increased  (Tables  IV  and  V) .  This  leads  to  an 
hypothesis  which  must  be  considered  in  seeking  an  explana- 
tion for  the  quantitative  sugar  changes.  The  pathologic 
picture  of  epidemic  encephalitis  is  essentially  one  of  the 
blood-vessels  and  the  perivascular  spaces.  It  seems  possible 
that  the  thin  membrane  of  cells,  which  normally  retains 
within  the  blood  a  greater  amount  of  sugar  (0.80  per  cent  to 
0.120  per  cent)  than  that  of  the  spinal  fluid  (0.040  per  cent 
to  0.060  per  cent)  may,  by  being  injured,  permit  the  amount 
of  sugar  in  the  spinal  fluid  to  approach  that  of  the  blood. 

The  occurrence  of  rapid  emaciation  during  the  encephalitic 
process  and  of  marked  adiposity  after  it  strongly  suggests 
metabolic  disturbances  dependent  on  endocrine  dysfunction. 
We  believe  that  the  observations  on  the  relations  of  striate 
lesions  to  creatinism,  the  presence  of  cirrhosis  of  the  liver  in 
progressive  lenticular  degeneration  (Wilson's  syndrome),  and 
of  genital  dystrophy,  similar  to  Frolich's  syndrome,  occur- 
ring in  midbrain  lesions,  are  of  great  importance  from  both 
a  theoretic  and,  perhaps,  a  clinical  point  of  view.  A  hypo- 
thalamic— vegetative    nervous    system — endocrine    connec- 

1  Aschner,  B. :  Zur  Physiologie  der  Zwischenhirns,  Wien.  klin.  Wchnschr., 
1912,  No.  25,  p.  1042.  Quoted  from  H.  Higier:  Vegetative  Neurology,  Nerv.  & 
Merit.  Dis.,  Monograph  Series,  1919,  No.  27,  p.  35. 


SYMPTOMATOLOGY  99 

tion,  seems  possible.  We  should  like  to  urge  an  investigation 
of  the  basal  metabolism  as  well  as  chemical  blood  examina- 
tions in  cases  of  epidemic  encephalitis  in  the  hope  of  obtain- 
ing more  definite  data  on  this  very  little  considered  subject. 

The  diagnostic  value  of  the  spinal  fluid  findings  in  epidemic 
encephalitis  is  mentioned  in  detail  in  the  section  on  differen- 
tial diagnosis.  The  combination  of  an  increase  of  cells, 
globulin  and  sugar  with  changes  in  the  colloidal  gold  curve 
constitutes  a  tetrad  of  laboratory  findings  of  diagnostic 
importance.  Findings  other  than  these  are  not  of  diagnostic 
importance  unless  related  to  the  clinical  findings. 

The  blood  picture  gives  evidence  of  a  type  of  infection 
which  does  not  call  forth  a  polymorphonucleosis.  It  does  not 
differ  essentially  from  the  picture  shown  by  other  similar 
toxemias  and  is  mostly  of  importance  in  differentiating 
from  organic  diseases  of  nontoxic  origin,  such  as  brain  tumor. 

The  following  questions  submitted  to  Dr.  Kraus  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Tilney:  Dr.  Kraus,  what  in  your  opinion  is  the  most 
important  single  feature  in  the  spinal  fluid  making  the  diagnosis 
of  epidemic  encephalitis? 

Dr.  Kraus  :  At  the  present  state  of  our  knowledge  of  the  various 
tests  which  can  be  done  on  the  spinal  fluid,  the  most  important 
thing,  I  think,  is  the  quantitative  sugar  determination.  I  should 
like  to  qualify  the  answer  by  saying  that  there  have  been  very 
few  if  any  reports  in  the  literature  about  the  spinal  sugar  in  other 
diseases,  so  that  the  conclusion  has  to  be  made  with  reservations. 

Dr.  Dana:  Have  the  authors  found  that  meningitis  reactions 
in  the  fluid  are  added  to  the  encephalitis  after  frequent  lumbar 
puncture? 

Dr.  Kraus:  We  have  been  unable  to  make  any  observations  on 
that  point. 

Dr.  Ayer:  What  does  the  differential  cell  count  in  spinal  fluid 
show? 

Dr.  Kraus:  We  attempted  to  clear  up  that  point  but  haven't 
been  able  to  do  it  quite  satisfactorily.  It  seems  that  at  the  begin- 


ioo  ACUTE  EPIDEMIC  ENCEPHALITIS 

ning  of  the  disease  there  is  a  tendency  for  the  number  of  poly- 
morphonuclears to  be  much  greater  than  at  the  later  stages  of  the 
disease,  and  Dr.  Pardee  in  reading  the  paper  mentioned  the  fact 
that  at  the  beginning  of  the  disease  about  15  per  cent  of  polymor- 
phonuclears are  very  frequently  present,  but  we  have  not  been 
able  to  get  the  time  relations  of  the  cell  counts  in  a  sufficient 
number  of  cases  to  warrant  our  making  that  a  definite  conclusion. 
That  seems  the  general  tendency. 

Dr.  Sachs  :  For  how  many  weeks  of  the  disease  would  the  sugar 
test  be  of  importance  according  to  your  experience? 

Dr.  Kraus:  During  the  entire  disease.  I  have  recently  seen  a 
case  beginning  in  February,  1920,  a  definite  case,  which  showed  a 
sugar  content  of  .95  about  two  weeks  ago  (December,  1920). 

Dr.  Dana:  Do  I  understand  that  you  found  no  particular 
differences  in  the  cell  count  as  a  result  of  frequent  repeated  lumbar 
puncture? 

Dr.  Kraus:  We  noticed  no  such  occurrence.  We  did  not 
notice  any  change  whatsoever  in  going  over  the  statistics  which 
we  had  on  hand  from  case  reports.  We  had  not  thought  of  that 
point  particularly,  but  nothing  in  that  connection  struck  us  in 
going  over  it. 

Dr.  Dana  :  Were  not  there  a  good  many  cases  under  observation 
where  repeated  lumbar  punctures  were  done? 

Dr.  Kraus:  Of  the  cases  which  we  saw,  I  should  say  that 
probably  40  cases  or  50  cases  had  repeated  punctures,  and  of  that 
number  not  more  than  10  perhaps  showed  an  increase.  Whether 
that  was  due  to  the  number  of  lumbar  punctures  or  due  to  change 
of  condition  of  the  brain  due  to  infection,  I  am  unable  to  say. 

Dr.  Taylor:  Dr.  Sachs  and  I  did  not  quite  understand  the 
colloidal  charts. 

Dr.  Kraus:  The  little  mountain  represents  the  change  in  the 
color,  and  the  millimeter  paper  is  so  arranged  that  one  millimeter 
in  the  horizontal  direction  is  equal  to  one  tube.  Two  millimeters 
in  the  vertical  direction  equal  a  change  of  say  from  one  to  two, 
or  two  to  three,  or  three  to  four  in  color  change. 

Dr.  Taylor:  Can  you  tell  us  briefly  what  the  characteristic 
curve  is? 

Dr.  Kraus:  There  is  no  really  characteristic  curve  in  any  point 
of  the  disease  as  far  as  we  were  able  to  determine  it.  The  so-called 
paretic  type  occurs  quite  frequently  and  the  type  of  low  curve 


SYMPTOMATOLOGY  i  o  i 

running  right  through  suggesting  a  meningitic  type  occasionally 
occurs.  We  were  unable  to  determine  any  definite  type  in  any 
of  these  cases  in  relation  to  time,  to  the  duration  of  the  disease, 
the  intensity  or  any  other  factors. 

Dr.  Taylor:  In  regard  to  pressure,  did  you  tabulate  the  pres- 
sure carefully?  Did  you  measure  it  in  millimeters  or  was  it  an 
assumption? 

Dr.  Kraus:  It  was  an  assumption  from  observation;  it  was 
not  measured. 

Dr.  Patrick:  May  I  inquire  if  you  have  done  any  sugar  deter- 
minations in  recovered  cases  after  the  symptoms  have  disappeared? 

Dr.  Kraus:  No,  sir,  because  we  have  never  seen  recovered 
cases.  As  a  matter  of  fact  the  sugar  determinations  that  we  have 
made  were  only  done  in  May  and  we  did  not  have  much  oppor- 
tunity in  the  summer  to  have  very  many  made,  which  accounts 
for  the  paucity  of  the  observations. 

CONCLUSIONS   OF   THE   COMMISSION 

The  Commission  submits  that  spinal,  radicular  and 
peripheral  nerve  involvements  in  epidemic  encephalitis  are 
common,  though  seldom  in  absolutely  clear-cut  forms,  and 
usually  accompanied  by  properly  speaking  encephalitic 
symptoms.  It  would  be  a  repetition  of  the  above  reports  to 
enumerate  reasons  for  these  conclusions  in  a  clinical  domain. 

The  spinal  type  of  the  disease  falls  into  two  forms:  the 
ventral  poliomyelitic  form  and  the  transverse  myelitic  form. 
The  former  is  subdivided  into  two  types,  an  irritative  type 
and  a  paralytic  type.  The  irritative  type  is  characterized  by 
movements  of  the  spinal  level  variety,  namely,  myoclonic 
and  fibrillary. 

The  irritative  type  of  spinal  involvement  cannot  be 
entirely  differentiated  from  a  radicular  localization,  which  is, 
strictly  speaking,  non-spinal.  Besides  the  radicular  type  of 
epidemic  encephalitis,  there  is  the  form  with  definite  periph- 
eral nerve  involvement. 

The  clinical  observations  to  date  are  almost  entirely  con- 
fined to  motor  and  sensory  phenomena.  The  behavior  of  the 


i02  ACUTE  EPIDEMIC  ENCEPHALITIS 

sympathetic  nervous  system,  especially  in  relation  to  tract 
implications,  in  the  true  spinal  types  remains  to  be  worked 
out. 

The  conclusions  in  the  laboratory  field  are  clearly  stated 
and  they  are  considered  properly  evaluated  in  the  report 
itself  on  this  phase. 


Chapter  IV 

SYMPTOMATOLOGY:  PSYCHOTIC  MANIFESTA- 
TIONS OF  EPIDEMIC  ENCEPHALITIS 

THE  material  of  this  chapter  is  reported  by  Drs.  George 
H.  Kirby  and  Thomas  K.  Davis  of  New  York  City, 
and  by  Dr.  Leslie  B.  Hohman,  of  the  Phipps  Psychiatric 
Clinic,  Johns  Hopkins  University.  This  chapter  deals  entirely 
with  the  psychotic  manifestations  of  lethargic  encephalitis. 
Dr.  Kirby's  and  Dr.  Davis'  material  is  from  the  institutions 
of  New  York  State  and  from  the  hospitals  of  New  York  City. 
Dr.  Hohman's  material  is  from  the  Phipps  Psychiatric  Clinic 
of  the  Johns  Hopkins  Hospital. 

Psychiatric  Aspects  of  Epidemic  Enxephalitis  (George 
H.  Kirby  and  Thomas  K.  Davis).  The  clinical  mate- 
rial available  for  this  study  comprises  18  cases  divided 
between  general  hospital  patients  and  patients  observed  in 
hospitals  for  the  insane.  They  are  all  cases  about  which  we 
feel  there  can  be  no  doubt  as  to  the  diagnosis  of  epidemic 
encephalitis.  In  each  case  we  were  able  to  get  a  fair  anamnesis, 
and  in  those  patients  who  have  left  the  hospitals  we  suc- 
ceeded in  obtaining  information  as  to  the  further  course  and 
outcome. 

The  wide  variety  of  terms  used  by  other  writers  to  desig- 
nate the  more  striking  psychotic  manifestations  of  enceph- 
alitis indicates  a  lack  of  any  generally  accepted  nosological 
viewpoint.  Few  observers  have  offered  any  systematic 
psychiatric  grouping  of  the  cases  studied.  Some  ignore  the 
mental  aspect  of  the  disease  and  adhere  to  a  strictly  ana- 
tomical classification,  while  others  group  their  cases  partly 
from  the  anatomical  and  partly  from  the  psychiatric 
standpoint. 

103 


104  ACUTE  EPIDEMIC  ENCEPHALITIS 

It  is  now  known  that  epidemic  encephalitis  is  an  acute 
or  subacute  inflammatory  disease  of  the  central  nervous 
system.  It  is  probable  that  the  disease  is  caused  by  an  infec- 
tious organism.  It  seems  reasonably  certain  that,  as  a  result 
of  the  activity  of  the  causative  agent  or  a  toxin,  a  varying 
degree  of  temporary  or  permanent  damage  to  the  cerebral 
tissues  takes  place.  As  a  consequence,  psychic  disturbances 
of  varying  degrees  of  intensity  arise. 

The  psychiatric  problems  of  epidemic  encephalitis  would, 
therefore,  appear  to  lead  directly  to  a  consideration  of  those 
types  of  mental  disturbance  capable  of  being  called  forth 
by  toxic  or  infectious  causes  which  act  deleteriously  on  the 
central  nervous  system.  From  the  standpoint  of  clinical 
differentiation  the  first  question  might  be,  What  are  the 
known  characteristics  of  mental  disorders  arising  on  such  an 
etiological  basis? 

The  studies  of  Meyer,  Bonhoeffer,  Hoch  and  Bleuler 
have  shown  that  disturbances  of  mental  function,  like  dis- 
turbances of  other  functional  mechanisms,  take  place  in  a 
relatively  limited  number  of  ways.  Clinical  studies  have  in 
fact  made  it  possible  to  circumscribe  a  fairly  small  number 
of  abnormal  mental  reaction  types  which  are  now  recognized 
to  be  of  fundamental  importance  in  all  questions  of  patho- 
genesis and  symptomatology  of  mental  disorders.  So  far  as  we 
can  see  at  present,  there  are  three  mental  reaction  types 
which  are  of  special  psychiatric  significance.  These  are: 
(i)  the  organic  reactions;  (2)  the  affective  reactions;  and 
(3)  the  trend  reactions. 

It  is  our  view,  based  on  pathology  and  probable  etiology, 
and  also  on  clinical  experience,  that  the  psychiatric  prob- 
lems of  epidemic  encephalitis  belong  essentially  in  the  realm 
of  the  organic,  more  specifically  the  toxic-infectious  mental 
reaction  types.  The  present  study  is  a  clinical  contribution 
in  affirmation  of  this  conception. 

The  features  common  to  all  psychoses  which  develop  as  a 
result  of  brain  disease,  or  injury  through  trauma,  infection, 
poisons,  etc.,  constitute  the  organic  syndrome.  The  organic 


S  YM  PTOM  ATOLOG  Y  i  o  5 

mental  reaction  may  be  acute  or  chronic.  The  essential 
elements  of  the  chronic  reaction,  encountered  in  all  of  the 
slowly  progressive  organic  brain  diseases,  are  well  known. 
These  are  impairment  of  mental  grasp,  difficulty  in  activiza- 
tion  of  memories,  defects  in  orientation  and  retention  with 
variability  in  mental  capacity  and  fluctuations  in  the  level  of 
attention,  the  so-called  mental  tension  defect. 

The  acute  organic  reactions  have  recently  become  better 
understood,  chiefly  as  a  result  of  Bonhoeffer's  work  on  acute 
Korsakoff's  disease,  and  deliria  accompanying  physical 
diseases.  The  typical  acute  organic  reactions  are  the  deliria 
due  to  trauma,  alcohol,  uremia,  infections,  bacterial  toxins, 
etc.  Brain  torpor,  somnolence  or  stupor  may,  however,  be 
the  most  striking  clinical  expression  of  the  reaction  replacing 
or  alternating  with  the  delirium.  In  the  acute  reaction  there  is 
difficulty  in  mental  grasp  and  interference  with  the  elabora- 
tion of  impressions  often  to  the  point  of  clouding  of  the 
sensorium;  also  orientation  and  retention  defects,  and  a 
striking  variability  in  the  level  of  consciousness;  when  low- 
ered, the  train  of  thought  becomes  fragmentary;  there  is  then 
muttering  and  incoherence.  With  clouding  of  consciousness, 
dream-like  ideas  and  hallucinations  appear  and  there  is  a 
marked  tendency  for  habitual  trends  of  thought  and  activi- 
ties to  dominate  the  scene — the  well-known  occupation 
delirium. 

The  more  common  clinical  manifestations  of  the  acute 
organic  reactions,  as  they  occur  in  psychiatric  practice,  are: 

1.  Acute  delirium:  the  organic  features  of  which  are 
plainly  evident. 

2.  States  of  psychic  torpor:  various  grades  of  mental 
dullness,  somnolence,  stupor  or  coma. 

3.  Amnestic-confabulatory  complex:  acute  Korsakoff 
syndrome. 

4.  A  group  of  more  complicated  psychotic  reactions  in 
which  organic  elements  are  combined  with  emotional  dis- 
orders, trends  and  psychomotor  disturbances  not  usually 
seen  in  the  more  typical  organic  syndromes.  In  these  more 


io6  ACUTE  EPIDEMJC  ENCEPHALITIS 

complex  cases  the  personality  traits  and  various  psychogenic 
reactions  come  more  to  the  front  and  thereby  give  a  special 
cast  to  the  clinical  picture. 

A  wide  range  of  neurological  syndromes  was  encountered 
in  our  series  of  cases,  but  we  were  not  able  to  make  any 
correlation  between  physical  types  and  the  form  or  outcome 
of  the  mental  disturbance.  In  the  following  we  give  a  brief 
analysis  of  the  psychotic  symptoms  most  prominent  in 
epidemic  encephalitis. 

Sleep  Disturbance.  Pathological  sleep  has  a  wide  occur- 
rence in  neuropsychiatric  conditions;  the  various  cerebral 
and  other  conditions  with  which  it  is  often  associated  need 
not  be  enumerated.  In  encephalitis  a  sleep  disturbance  is 
the  most  obvious  mental  alteration,  and  we  found  in  all  our 
cases  a  period  of  pathological  drowsiness  at  some  stage  of 
the  disease.  The  sleep  disturbance  is  best  put  in  terms  of 
hyper-  and  hypo-function,  for  in  this  way  it  will  be  quickly 
brought  to  mind  that  not  all  cases  of  encephalitis  show 
somnolence.  On  the  hyperfunction  side  it  is  serviceable  to 
recognize  four  gradations:  drowsiness,  lethargy,  stupor  and 
coma.  The  differences  are  those  of  degree.  A  very  striking 
feature  of  the  lethargic  states  is  the  ease  with  which  the 
patients  may  be  usually  aroused  and  the  brightness  and 
alertness  then  often  shown.  Such  a  reaction  is  not  so  fre- 
quently seen  in  other  toxic-organic  somnolent  states,  but 
even  in  encephalitis  it  is  apparently  a  question  of  degree  or 
depth  of  the  disturbance,  as  stuporous  patients  very  often 
cannot  be  aroused  or  if  they  can  be,  they  show  plainly  that 
they  are  unclear  or  confused. 

Certain  cases  in  an  immobile  state,  with  mask-like  facies, 
mutism  and  open  eyes,  emphasize  the  fact  that  the  sleep 
disturbance,  so-called,  is  only  partly  an  alteration  in  the 
level  of  consciousness  and  that  with  it  there  is  an  activity 
disturbance.  (This  will  be  referred  to  again  under  motor 
phenomena.) 

Hyposomnia  or  insomnia,  noted  by  some  as  an  onset 
symptom,  occurs  in  a  majority  of  cases  later,  if  at  all.  It 


SYMPTOMATOLOGY  1 07 

is  frequently  accompanied  by  an  intense  psychic  over- 
activity. 

Hypersomnia  and  hyposomnia  may  alternate  in  the  same 
patient  through  a  definite  day  and  night  cycle  with  a  rever- 
sal, however,  of  the  usual  order. 

The  various  theories  advanced  to  explain  the  causation 
of  the  alterations  of  sleep  do  not  adequately  account  for 
all  the  clinical  features  encountered  in  our  cases,  particularly 
the  alternating  combinations  of  hyper-   and  hyposomnia. 

Delirium.  The  second  most  common  feature  of  the 
mental  picture  is  delirium.  The  delirium  of  encephalitis 
presents  the  general  characteristics  of  an  acute  organic 
disturbance.  It  is  usually  not  prolonged  and  may  in  fact  be 
limited  to  fleeting  delirious  episodes,  especially  at  night. 
Transient  delirious  features  during  lethargy  or  stupor  may  be 
easily  overlooked.  The  content  of  the  delirium  tends  to 
center  about  habitual  trains  of  thought  and  the  usual  daily 
activities  of  the  patient,  while  in  some  instances  it  is 
determined  by  disagreeable  somatic  sensations.  Combined 
hallucinations  and  illusionary  falsification  of  things  in  the 
immediate  environment  are  prominent.  The  recollection 
of  the  delirious  trains  of  thought  may  be  quite  well  pre- 
served upon  recovery  while  there  is  partial  or  complete 
amnesia  for  external  events. 

Emotional  Reactions.  The  extremely  wide  range  of 
emotional  reactions  met  with  indicates  that  the  differences 
between  individual  cases  are  very  great  or  that  the  mood 
varies  markedly  through  the  different  stages  of  the  disease. 

In  the  early  stages,  before  the  onset  of  the  torpor  or 
delirium,  marked  mood  changes  were  not  often  encountered. 
Pronounced  depression  is  not  frequent  at  the  beginning. 
Euphoria  and  overactivity  are  at  times  present  at  this  stage, 
but  they  are  more  apt  to  be  a  later  development,  following 
the  delirium  or  stupor.  Euphoria  with  added  features  of  a 
manic  state  occurs  and  furnishes  a  picture  not  distinguish- 
able from  a  manic-depressive  excitement. 

In  the  lethargic  and  stuporous  phases  the  most  charac- 


io8  ACUTE  EPIDEMIC  ENCEPHALITIS 

teristic  emotional  state  is  apathy,  which  may  be  extreme. 
However,  just  as  a  patient  may  be  aroused  from  the  sleep,  so 
may  he  usually  be  aroused  by  strong  emotional  stimuli  to 
show  an  appropriate  affective  reaction. 

We  have  also  observed  peculiar,  and  in  a  sense  contra- 
dictory, emotional  reactions  in  patients  still  unrecovered; 
one  patient  exhibits  a  markedly  apathetic  state  which  is 
spontaneously    interrupted    by    singing    and    jig-dancing; 
another  patient  in   a   suicidal   depression,   talks   of  being 
killed,  yet  she  can  be  easily  induced  to  smile  or  laugh  a 
little.  This  emotional  lability  seems  not  to  be  fully  under 
her  control  and  the  patient  has  remarked  that  she  knows  it 
is   "foolish"   to   smile.   These  unusual  mood   reactions   in 
certain  cases  suggest,  at  least  superficially,  a  lack  of  cor- 
respondence between  the  affect  and  ideas  expressed.  We 
have  not  found,   however,   dissociation  of  affect  such   as 
occurs  in  schizophrenia.   It  is  rather  the  quick  change  of 
mood  that  is  misleading,  but  with  these  changes  there  seems 
to  be  always  a  corresponding  change  in  ideational  content. 
What  appears  to  us  to  be  a  very  significant  observation 
is  the  persistence,  in  a  large  majority  of  cases,  of  emotional 
alterations   or   changes   in   character   noticeable   after   the 
acute  stages  of  encephalitis  have  passed,  in  many  instances 
after   recovery   seemed   otherwise   to   have   been   reached. 
These,  so  to  speak,  emotional  residuals  appear  in  varied  form : 
in  some  cases  the  change  is  in  the  direction  of  a  depressive 
affect,  in  others  in  the  direction  of  an  emotional  elevation  or 
irascibility,  in  still  others  explosive  reactions,  stubbornness, 
apathy,  etc.,  are  reported.  The  question  has  arisen,  therefore, 
in  many  cases  as  to  whether  or  not  a  permanent  damage  has 
occurred  in  the  emotional  sphere. 

Motor  Phenomena.  From  what  we  have  learned  regarding 
the  sleep  disturbance  and  the  affectivity  during  the  lethargy 
of  encephalitis,  we  believe  that  the  psychic  torpor  and  emo- 
tional apathy  are  the  most  important  mental  factors  in 
producing  the  stupor,  while  the  rigidity  and  certain  other 
muscular  symptoms,  when  they  occur  during  the  stupor,  are 


SYMPTOMATOLOGY  1 09 

the  expression  of  a  motor  phenomenon  of  the  sort  seen  in  paral- 
ysis agitans.  The  tendency  to  hold  given  positions  (catalepsy) 
seems  to  be  most  often  associated  with  Parkinsonian  symp- 
toms, especially  rigidity.  We  have  not  observed  any  symp- 
toms of  catatonic  negativism  in  encephalitis  cases,  although 
it  is  well  known  that  negativistic  phenomena  may  occur  in 
toxic-infectious  disorders  and  in  emotional  settings  other 
than  dementia  praecox.  We  have  not  seen  spring-like  resis- 
tance, release  of  an  opposite  impulse,  fantastic  postures, 
clenched  fists,  "  schnauzkrampf, "  or  cyanosis  of  the  extremi- 
ties. On  the  other  hand,  mutism,  drooling  of  saliva,  holding 
of  urine,  wetting  and  soiling  the  bed  occur  in  the  stupor  of 
encephalitis  and  may  be  mistaken  for  negativistic  reactions. 
To  us  it  has  appeared  more  plausible  to  bring  them  into 
relation  with  the  psychomotor  inertia  and  emotional  apathy, 
a  view  which  is  supported  by  the  patients'  explanations 
obtained  after  emergence  from  the  period  of  inactivity  or 
stupor.  The  use  of  the  term  "catatonia"  in  describing 
motor  or  muscular  phenomena  of  encephalitis  seems  to  us  to 
be  misleading. 

Psychotic  Trends  and  General  Mental  Content.  Ideas  of  a 
specific  type  are,  of  course,  not  to  be  expected  in  encephalitis 
any  more  than  in  other  organic-infectious  mental  disorders. 
One  has  only  to  recall  the  multiplicity  of  delusional  ideas 
encountered  in  syphilitic  encephalitis  or  paresis,  where  such  a 
great  diversity  of  clinical  pictures  arises  with  brain  changes 
of  a  very  definite  and  specific  character.  Transient  delusions 
or  fixed  ideas,  independent  of  the  delirium,  do  occur,  but  in 
general  we  may  say  that  definitely  formulated  and  persistent 
delusional  trends  are  infrequent  in  the  course  of  an  enceph- 
alitis. Our  series  includes  two  fairly  clear  schizophrenic 
reactions  one  of  which  had  begun  prior  to  the  encephalitis. 

Mental  Grasp,  Orientation  and  Memory.  Observers  usually 
say  that  when  patients  can  be  aroused  from  lethargy  or  even 
stupor,  that  they  are  often  remarkably  clear  as  to  their 
environment,  etc.  The  degree  of  clearness  can,  however,  vary 
a  great  deal  even  within  a  short  space  of  time.  A  patient  in  a 


no  ACUTE  EPIDEMIC  ENCEPHALITIS 

lethargic  or  stuporous  state  may  sink  at  any  time  to  a  lower 
level  of  consciousness,  mutter  and  show  "delirious  dips" 
for  a  short  or  longer  period.  We  have  found  on  closer  exami- 
nation of  awakened  patients  that  although  they  may  be 
generally  clear  as  to  the  environment  and  recognize  those 
about  them,  there  are  nevertheless  evidences  of  interference 
with  the  mental  processes  and  difficulty  in  grasp  of  more 
complicated  things.  This  we  interpret  as  a  mental  tension 
defect,  such  as  occurs  in  organic  reactions  generally.  We 
have  found  in  our  cases  very  little  evidences  that  any  severe 
or  lasting  impairment  of  orientation  or  memory  follows  the 
acute  stages  of  the  disease.  The  absence  of  any  intellectual 
deterioration  or  dementia  is  especially  noteworthy. 

Briefly  Put,  the  Conclusions  Which  we  Are  Inclined  to  Draw 
From  our  Study  Are  as  Follows:  The  psychic  disturbances  of 
epidemic  encephalitis  present  the  general  characteristics 
of  an  acute  organic  type  of  mental  reaction  corresponding 
more  precisely  to  the  group  of  toxic-infectious  psychoses. 

In  the  acute  stages  of  the  disease,  pathological  sleep, 
delirium  and  various  mood  alterations  are  the  most  striking 
mental  disturbances,  although  other  clinical  pictures  may 
be  encountered,  as  the  Korsakoff  syndrome,  or  more  complex 
mental  disorders  in  which  various  affective  and  trend  reac- 
tions  add   special   features  to   the   psychotic    disturbance. 

Although  the  mental  disturbance  is  essentially  of  the 
acute  organic  type,  this  tends  to  recede  as  the  early  stages 
of  the  disease  are  passed;  no  marked  mental  reduction, 
intellectual  impairment  or  dementia  has  so  far  occurred  in 
any  of  our  cases.  On  the  other  hand,  we  have  found  a  great 
deal  of  evidence  of  persisting  emotional  alterations.  In  the 
majority  of  cases  which  have  left  the  hospitals  this  emotional 
alteration  constitutes  practically  the  only  evidence  of  a  lack 
of  mental  recovery. 

We  are  inclined  to  think  that  there  is  a  special  tendency 
for  the  emotional  mechanisms  to  be  directly  or  indirectly 
disturbed  in  encephalitis.  As  to  the  permanence  of  this 
alteration   or   damage,    we   cannot   as   yet  give  a  definite 


SYMPTOMATOLOGY  1 1 1 

opinion.  Whether  or  not  these  cases  will  later  on  show 
evidences  of  an  (organic)  mental  deterioration  is  a  question 
which  we  must  also  leave  open  for  future  determination. 

The  following  questions  submitted  to  Drs.  Kirby  and 
Davis  before  the  Commission,  together  with  the  answers  to 
them,  are  here  reported  verbatim. 

Dr.  Sachs:  I  would  like  to  ask  Dr.  Kirby,  who  has  no  doubt 
had  great  experience  in  all  forms  of  pathological  drowsiness  and 
stupor,  whether  there  was  something  about  the  stupor  of  the  epi- 
demic encephalitis  cases  that  struck  him  as  rather  different  from 
the  average  case  as  one  sees  it?  In  other  words,  is  there  not  some- 
thing peculiar  in  the  fact  that  a  person,  who  appears  to  be  in  as 
deep  a  stupor  as  the  average  lethargic  encephalitis  case,  is  yet 
able  to  respond  with  considerable  force,  almost  immediately  to  a 
question  put  him?  Isn't  that  something  that  differentiates  the 
stupor  or  the  lethargy  of  these  cases  from  the  lethargy  as  observed 
in  other  forms  of  mental  disease? 

Dr.  Kirby:  I  think  in  a  considerable  number  of  cases  that  is 
very  striking  and  probably  is  not  duplicated  in  other  organic 
reactions.  On  the  other  hand,  the  ability  to  show  mental  clearness 
varies  a  great  deal.  Some  cases  one  cannot  arouse,  and  whether 
or  not  it  is  simply  a  question  of  degree  or  intensity,  is  something 
which  perhaps  one  ought  to  take  into  consideration. 

Dr.  Sachs:  May  I  ask  one  more  question?  If  Dr.  Kirby  were 
asked  to  speak  of  the  most  striking  psychotic  after-effect  of  epi- 
demic encephalitis,  would  he  perhaps  allow  that  the  persistent 
depression  was  as  characteristic  as  any  other,  or  is  there  any  other 
psychotic  state  that  he  would  mention? 

Dr.  Kirby:  There  is  an  emotional  residual  which  I  have  referred 
to  and  which  we  think  is  one  of  the  most  significant  after-effects 
of  the  disease,  and  in  a  great  majority  of  cases  I  think  that  change 
is  in  the  direction  of  a  depressive  effect,  a  distinct  depression  which 
sometimes  may  be  hard  to  differentiate  from  an  apathy  unless  one 
examines  the  patient  carefully.  I  have  been  rather  struck  by  the 
absence  of  any  special  feeling  of  sadness  in  this  depression,  and 
in  that  way  it  seems  rather  to  differentiate  from  the  more  typical 
depressing  conditions.  The  patients,  although  depressed,  seem 
rather  free  from  any  special  sadness  or  hopelessness  regarding 
their  future. 


ii2  ACUTE  EPIDEMIC  ENCEPHALITIS 

We  have  had  some  very  interesting  cases.  Boys  have  shown  a 
very  marked  change  ot  character.  After  the  disease,  they  have 
become  emotionally  unstable,  very  pugnacious,  irascible,  and 
quite  a  problem  in  the  family.  One  patient  is  so  disturbed  that 
he  is  remaining  in  the  hospital.  In  fact,  it  is  rather  significant — 
after  a  period  of  several  months  he  has  had  a  convulsion,  which, 
of  course,  would  indicate  what  I  would  call  an  organic  foundation. 

Dr.  Sachs:  One  more  question.  Have  you  seen  any  case,  Dr. 
Kirby,  in  which  a  more  or  less  chronic  psychosis  has  been  influenced 
to  the  good  by  the  appearance  of  any  epidemic  encephalitis? 

Dr.  Kirby:  No,  I  have  not  seen  any. 

Dr.  Taylor:  Dr.  Mulhouse  offers  the  following  question: 
Is  the  emotional  residuum  any  different  from  that  seen  after 
influenza? 

Dr.  Kirby:  The  depressive  tendency  is  very  much  like  that 
which  follows  in  influenza.  I  haven't  seen  after  influenza  these 
peculiar  elevating  mood  reactions  persisting  for  such  a  long  time. 

Dr.  Taylor:  Apropos  of  Dr.  Sachs'  first  question  regarding 
the  nature  of  the  lethargy — whether  it  is  analogous  to,  or  a  degree 
of,  normal  sleep, — did  the  patients  have  any  recollection  of  the 
events  during  the  lethargy? 

Dr.  Kirby  :  That  is  an  interesting  point.  The  patients  remember 
a  great  deal  of  what  they  thought  about  during  the  lethargy, 
and  if  they  had  any  delirium  they  remember  the  content  of  the 
delirium,  but  they  don't  remember  where  they  were  or  their 
movements  or  any  external  events.  That  in  a  way  is  rather  different 
from  the  psychogenic  delirium  where  patients  very  often  forget 
entirely  their  delirious  trends. 

Dr.  Taylor:  Would  that  not  also  separate  it  from  a  degree 
of  normal  sleep  and  make  it  more  or  less  a  specific  type? 

Dr.  Kirby:  It  might  unless  we  thought  of  the  normal  dream 
as  being  constructed  somewhat  like  a  delirious  experience. 

Dr.  Barker:  Has  Dr.  Kirby  found  that  encephalitis  is  more 
common  in  persons  with  an  alcoholic  history? 

Dr.  Kirby:  We  had  only  one  in  our  series  of  18  cases  in  which 
there  was  an  alcoholic  history.  We  haven't  noticed  that. 

Dr.  Barker:  Has  there  been  any  difficulty  in  institutions  for 
mental  diseases  in  recognizing  encephalitis  in  outspoken  psychosis 
like  dementia  praecox? 

Dr.  Kirby  :  I  think  our  experience  has  been  that  there  have  been 


SYMPTOMATOLOGY  1 1 3 

cases  passing  through  the  institutions  that  were  not  recognized 
until  they  came  to  autopsy.  On  the  other  hand,  in  the  New  York 
State  Hospital,  it  might  be  rather  interesting  to  report,  that 
among  6,500  patients  admitted  during  the  hospital  year  there 
were  20  cases  in  which  the  diagnosis  was  made  of  encephalitis, 
probably  not  all  definitely  confirmed.  So  that  the  number  of 
cases  with  severe  psychotic  manifestations  arriving  in  the  state 
hospitals  seems  to  be  relatively  small. 

Dr.  Barker:  Dr.  Thomas  in  Baltimore  has  noticed  a  number 
of  children  who  have  had  a  persistent  mental  reduction  after  the 
attack.  Has  that  been  common  here? 

Dr.  Kirby:  We  have  had  only  two  children  in  the  series,  and 
in  both  of  them  their  mental  after-effects  were  decidedly  of  an 
exaggerated  emotional  type — hypomanic  tendency.  We  have 
tried  to  make  very  careful  examinations  of  some  severe  psychotic 
patients  that  have  been  several  months  in  a  hospital  to  see  whether 
or  not  there  was  any  mental  reduction  in  the  sense  of  a  deteriora- 
tion of  the  intellectual  faculties.  We  found  that  when  a  patient's 
attention  and  cooperation  could  be  obtained  he  did  remarkably 
well  on  all  the  thinking  and  intellectual  tests.  It  was  very  striking. 
One  man  in  a  very  marked  state  of  indifference  could  retain  and 
could  do  mental  operations  in  quite  an  unusual  way,  showing 
that  he  was  able  to  bring  out  emotional  actions.  At  times  one  can 
also  bring  a  patient  to  a  higher  life  of  intellectual  activity  by  a 
stimulant. 

Dr.  Barker:  In  men  past  middle  life  we  have  had  a  few  cases, 
thought  by  neurologists  and  psychiatrists  to  be  either  cerebral 
atherosclerosis  or  dementia  paralytica,  which  afterwards  turned 
out  to  be  encephalitis.  Has  that  been  frequent  in  your  experience? 

Dr.  Kirby:  Several  of  our  cases  were  considered  in  the  beginning 
to  be  paresis.  I  mean  on  initial  review.  We  haven't  had  any  athero- 
sclerotic complications  in  our  cases. 

Dr.  Hunt:  I  would  like  to  ask  if  these  psychotic  types  had 
associated  with  them  other  paralytic  symptoms?  Were  those 
severe  or  were  any  of  them  of  pure  psychotic  types  indicating 
perhaps  only  cortical  involvement,  and  have  there  been  any  autop- 
sies in  the  psychotic  types? 

Dr.  Kirby:  We  have  not  seen  any  very  marked  paralytic 
symptoms.  We  have  seen  some.  One  patient  had  a  peculiar  altera- 
tion of  speech  which  disappeared.  Our  autopsy  experience  has  not 


ii4  ACUTE  EPIDEMIC  ENCEPHALITIS 

been  very  extensive.  We  have  had  about  5  cases  sent  for  examina- 
tion. The  complete  working  up  of  that  material  has  not  been 
accomplished  yet.  I  do  not  think  I  would  be  prepared  to  say  very 
much  about  the  findings  now. 

Dr.  Hunt:  The  point  I  wanted  to  bring  out  was  whether  any 
of  your  cases  in  the  earlier  period  were  regarded  as  a  spinal  type 
or  radicular  type  or  cerebellar  type  or  basal  ganglia  type  or  cranial 
nerve  paralysis? 

Dr.  Kirby:  We  had  a  fairly  representative  group  from  the 
physical  side.  I  did  not  say  anything  about  that  in  the  summary, 
but  I  think  I  have  the  facts  of  that  here  in  my  paper. 

Dr.  Timme:  May  I  ask  if  any  metabolic  or  biochemical  studies 
have  been  made  on  your  cases? 

Dr.  Kirby:  None  have  been  made. 

Dr.  Timme:  Have  observations  been  made  as  to  any  of  these 
points  regarding  the  rapidly  changing  clinical  pictures  such  as  those 
you  have  mentioned  from  stupor  to  activity?  Are  any  observations 
made  on  the  patients  in  those  two  rapidly  changing  states? 

Dr.  Kirby:  The  question  of  the  variability  of  the  patient  as  to 
clearness,  we  have  gone  into,  and  the  question  of  the  transitory 
delirious  types  or  delirious  manifestations  we  have  tried  to  get  the 
records  of,  and  we  have  been  impressed  by  the  abrupt  changes, 
not  only  the  emotional  reactions  but  the  level  of  consciousness 
which  these  patients  show.  On  one  occasion  a  patient  may  be  quite 
able  to  give  good  information;  on  another  occasion  he  may  appear 
decidedly  less  capable,  more  confused. 

Dr.  Timme:  Have  you  made  any  observations,  not  particularly 
in  your  records,  but  will  your  memory  serve  you  to  let  us  know 
the  changes  perhaps  in  blood-pressure  or  pulse  rate,  showing 
changes  on  a  level  not  only  psychic  but  also  vegetative  in  your 
experience? 

Dr.  Kirby:  I  am  afraid  we  have  not  very  many  observations 
that  we  could  use  in  that  connection.  The  routine  blood-pressure 
was  taken  in  a  good  many  of  the  cases ;  but,  as  regards  the  question 
of  fluctuations,  I  doubt  if  our  data  would  be  sufficient  to  allow  me 
to  answer. 

Dr.  Aronson:  I  would  like  to  ask  Dr.  Kirby  whether  he  has 
observed  hypersomnia  in  cases  ot  encephalitis  Iethargica  in  which 
the  amount  or  degree  of  sleep  suggested  to  him  a  relation  to 
possible  pituitary  involvement,  congestive  or  perhaps  inflam- 
matory? Somnolence  has  been  found  in  relation  to  some  types  of 


SYMPTOMATOLOGY  1 1 5 

pituitary  affection,  and  on  the  other  hand,  many  cases  of  epidemic 
encephalitis  have  shown  considerable  acromegalic  disturbance 
either  in  the  facies  or  in  the  extremities.  Have  you  any  memory 
of  these  conditions? 

Dr.  Kirby:  I  fear  not.  There  are  various  theories  regarding 
the  lethargy  and  sleep;  one  has  to  take  into  consideration  the 
activity  of  the  pituitary,  etc.,  but  we  really  haven't  any  obser- 
vations of  any  marked  change  in  the  general  physical  symptoms 
indicating  that  the  pituitary  has  been  involved. 

Dr.  Barker:  Marie  published  a  paper  specially  on  the  pituitary 
histological  changes,  and  his  conclusion  was  that  they  were 
noticeably  absent — less  than  would  have  been  expected. 

An  Analysis  of  the  Psychotic  Manifestations  of  23 
Cases  of  Epidemic  Encephalitis,  which  Were  Admitted 
to  the  Phipps  Psychiatric  Clinic  from  the  Spring  of 
19 19  to  the  Summer  of  1920  (Leslie  B.  Hohman).  Eight 
symptom  complexes  were  observed  and  are  presented  in  the 
order  of  their  diagnostic  importance. 

1.  Great  Push  of  Talk  Without  Distortion  oj  the  Stream  of 
Talk  and  Without  Mood  Alteration.  This  symptom  was  first 
called  to  our  attention  as  a  residual  by  Case  14.  When  given 
the  slightest  opportunity,  the  patient  poured  forth  a  minute, 
detailed  description  of  all  of  his  thinking  and  feeling.  At  first 
his  talk  was  concerned  with  the  material  of  his  delirium  and 
later  with  the  discussion  of  the  disease,  its  symptomatology, 
treatment,  etc.  The  only  possible  way  of  stopping  his  talking 
was  to  keep  everyone  out  of  earshot.  After  four  months  of 
the  disease,  this  was  the  only  symptom  persisting.  In  Case  10, 
this  was  the  only  abnormality  observed  which  gave  any  clue 
to  the  diagnosis.  The  second  patient  was  quite  clear  but 
seemed  unable  to  control  the  incessant  flow  of  words.  The 
manic  type  of  association — flight  of  ideas,  distractibility, 
etc. — has  not  been  present,  nor  does  the  mood  show  altera- 
tions to  account  for  the  talking.  The  patients  are  distractible 
and  it  is  difficult  to  break  in  on  the  stream  of  utterance 
and  divert  the  topic  of  conversation  to  other  channels. 
Increase  of  general  activity  has  been  absent.  One  feels  as  if 


n6  ACUTE  EPIDEMIC  ENCEPHALITIS 

all  inhibitions  to  silence  were  off;  the  flood-gates  are  down 
and  some  force  seems  to  drive  from  behind.  In  our  cases  this 
symptom  was  present  in  8  cases. 

2.  Euphoria,  Jocularity,  and  Feeling  oj  Well-being.  This 
has  been  one  of  the  most  striking  symptoms.  Thirteen  of  our 
cases  (i,  2,  3,  5,  6,  8,  9,  10,  11,  12,  13,  14,  and  23)  have  shown 
this  at  one  time  or  another  during  the  course  of  the  disease. 
This  sense  of  well-being  reminds  one  in  some  respects  of  the 
euphoria  of  the  paretic,  but  the  cheerfulness  does  not  seem  as 
empty  and  vacuous  as  that  of  the  paretic. 

3.  Alertness  and  mental  clearness,  when  the  patient  is 
once  aroused  in  spite  of  the  presence  of  stupor  and  somnolence. 

When  the  disease  first  began  to  be  seen,  one  was  amazed 
when  the  patient  dropped  off  to  sleep  during  examination. 

The  clearness  and  alertness  which  the  patients  show 
immediately  upon  being  aroused  from  their  sleep  is  equally 
surprising.  One  would  not  expect  as  much  wide-awakeness 
from  a  normal  person  aroused  from  sleep.  It  is  probably  true 
that  the  somnolence  appears  deeper  than  it  really  is  because 
of  the  ptosis  that  so  frequently  exists. 

4.  Delirium.  Delirium  has  been  noted  in  14  and  possibly 
15  of  our  cases.  This  term  is  used  to  describe  any  psychosis 
in  which  there  is  a  dreamy  state  with  clouding  of  con- 
sciousness, disorientation  and  a  type  of  association  in 
which  drifting  and  groping  are  present.  Following  Hoch's 
classification  of  the  deliria  as  organic  and  psychogenic, 
it  was  found  that  practically  all  of  our  cases  fell  into  the 
organic  group.  The  content  of  the  delirious  utterances 
concerned  itself  almost  exclusively  with  topics  which  did  not 
involve  the  personality  of  the  patient  in  any  of  the  instinctive 
realms.  Occupation  delirium  was  the  most  common  type  seen 
(Cases  1,  5,  6,  9,  13,  14,  19,  21),  and  this  has  been  the  rule  in 
cases  reported  by  other  observers.  In  3  of  our  cases  (14,  15, 
16)  the  delirium  was  accompanied  by  an  affect  of  fear. 

5.  Stupor  States.  Frequently  at  the  onset  of  the  disease 
stupor  states  have  been  observed  (5  of  our  cases).  These 
stupor    reactions    have    been    mistaken    for    schizophrenic 


SYMPTOMATOLOGY  1 1 7 

stupors.  However,  it  seems  to  us  that  the  schizophrenic 
makes  use  of  voluntary  motor  mechanisms  and  there  is 
rarely  observed  the  incoordinate  tremor  and  tonic  rigidity 
seen  in  the  encephalitic  stupor.  In  addition,  the  stupor 
does  not  arise  in  a  schizophrenic  setting.  Again,  the  clearness 
of  the  catatonic  stupor  is  absent. 

6.  Behavior  Oddities.  Impulsive  or  unusual  acts  totally 
out  of  keeping  with  the  rest  of  the  activity  of  the  patient 
have  been  seen  in  7  cases.  This  is  as  one  would  have  ex- 
pected in  any  psychosis  having  an  organic  basis.  The  impul- 
siveness of  the  paretic  and  arteriosclerotic  groups  is  well 
known.  Frequently,  however,  the  oddity  has  been  so  unusual, 
unmotivated,  and  in  some  cases  so  silly  that  it  has  impressed 
the  observer  as  being  significant.  For  instance;  Case  3 
tried  to  commit  sucide  by  hanging  herself  with  a  shoe  string 
without  any  real  desire  to  kill  herself.  Case  1  got  out  of  bed 
suddenly,  dashed  down  the  long  corridor,  and  when  brought 
back  said,  "Why  do  I  do  things  like  this?"  She  was  not 
frightened  and  the  act  seemed  totally  unmotivated.  Case  2 
bathed  practically  the  entire  day,  wrote  an  extraordinary 
number  of  letters,  and  took  huge  doses  of  cathartics.  Case  1 1 
showed  a  very  odd,  stilted  talk,  using  words  in  a  high-flown, 
silly  manner.  In  the  midst  of  a  formal  conversation  he  would 
swear  violent  oaths  without  any  anger.  Case  13,  although  he 
had  been  in  bed  for  weeks  and  was  very  somnolent  most  of 
the  time,  would  get  up  suddenly,  go  to  his  wardrobe,  pack 
his  suit-case  and  announce  that  he  was  leaving  for  home. 
Case  15  attempted  suicide  on  two  occasions  by  actually 
walking  out  of  the  third  story  window.  Case  16  had  temper 
tantrums  without  precipitating  causes  and  totally  out  of 
keeping  with  her  former  disposition.  Case  17  would  get  out 
of  bed  and  wander  about  looking  for  medicine.  She  was  not 
delirious  and  knew  well  that  she  was  in  isolation. 

7.  Depression  Has  Been  Observed  in  Seven  Cases.  In 
our  Cases  6,  7,  21,  it  was  a  transitory  symptom  but  was  pro- 
nounced and  prolonged,  in  fact  dominating  the  clinical 
picture  in  Cases  15,  16,  18  and  20.  Suicidal  attempts  have 


n8  ACUTE  EPIDEMIC  ENCEPHALITIS 

been  frequent  and  at  least  2  cases  were  brought  to  the 
hospital  for  just  this  reason.  In  Case  15  there  was  the  formal 
alteration  of  thinking  and  activity  which  characterizes 
the  manic  depressive,  i.  e.,  slowness  of  thinking  and  talking, 
morning-evening  variation,  etc.  Case  17  showed  a  deal  of 
puzzling  bewilderment  and  fear  as  well  as  depression.  In 
Cases  18  and  20  there  was  no  slowing. 

8.  Emotional  Instability  and  irritability  have  been  very 
frequent  incidents  of  the  disease,  especially  the  latter. 
Tantrums  and  anger  outbursts  have  occurred  without  obvious 
cause.  The  lability  and  overflow  of  emotional  response  has 
suggested  a  pseudobulbar  syndrome  in  Cases  1,  5,  8,  9. 

9.  Memory  Deject.  It  was  rather  surprising  to  find  no 
little  evidence  of  real,  permanent  memory  defects  in  our 
cases,  since  we  are  dealing  with  a  disease  in  which  there  is 
demonstrable  alteration  of  brain  substance.  In  all  four 
cases  (8,  11,  13,  22)  in  which  memory  defect  was  demon- 
strated (of  course  the  acute  deliria  are  excluded)  the  prime 
difficulty  was  in  recent  and  immediate  (retention)  memory. 
Case  8  in  addition  confabulated  freely.  With  an  alchoholic 
history  this  case  might  easily  have  passed  as  a  Korsakoff  syn- 
drome. All  forms  of  our  cases  showed  a  preliminary  period 
of  delirium  with  recent  memory  and  retention  difficulty. 

In  our  cases,  four  main  reaction  types  can  be  made  out: 

1.  Depressive. 

2.  Psychoneurotic-Iike. 

3.  Delirious. 

4.  Organic. 

The  same  interesting  inquiry  arises  here  as  in  the  con- 
sideration of  psychoses  due  to  the  parenchymatous  lues. 
Why  should  one  patient  react  with  a  manic  excitement, 
another  with  a  depressive  reaction,  and  a  third  with  a 
paranoid  or  a  classical  picture  of  general  paralysis? 

Unfortunately  the  post-mortem  findings  offer  us  no  expla- 
nation. We  are  of  the  opinion  that  with  diffuse  organic 
change  the  personality  and  constitution  of  the  patient  is 


SYMPTOMATOLOGY  1 19 

apt  to  run  amuck  at  its  points  of  greatest  vulnerability. 
That  is,  a  personality  or  constitution  which  is  able  to  main- 
tain an  adequate  adjustment  with  the  proper  repression 
or  sublimation  of  unsocial  trends  or  strong  instinctive 
drives  breaks  along  these  lines  when  the  automaticity  of 
adjustment  is  interfered  with.  Some  of  our  cases  bear  out 
this  notion  admirably. 

1.  Depression  Reaction  Type.  In  7  cases  this  type  of 
reaction  was  observed,  but  in  only  2  cases  were  there  the 
formal  thinking  and  activity  alterations,  i.  e.,  slowness  of 
the  manic-depressive  reactions.  The  other  cases  resembled 
the  reactive  and  psychoneurotic  depressions.  The  depression 
has  usually  been  admixed  with  short  phases   of  delirium. 

2.  Psychoneurotic-like  Reaction  Type.  Several  of  our  cases 
were  admitted  to  hospital  with  the  diagnosis  of  hysteria  or 
functional  disorder.  The  clinical  picture  in  several  cases  was 
gastric,  abdominal,  and  thoracic  hypochondriasis.  Careful 
physical  and  laboratory  examinations  revealed  no  cause  for 
these  complaints.  Suggestive  therapy  often  relieved  symp- 
toms, but  we  were  inclined  to  regard  them  as  probably 
due  to  actual  if  slight  organically  determined  functional 
deviations.  Our  attitude  has  been  to  treat  them  as  psycho- 
neurotic because  these  features  offered  more  chance  for 
therapeutic  aid  than  did  organic  alteration. 

3.  The  delirious  reaction  type  has  already  been  discussed 
under  symptomatology. 

4.  The  organic  reactions  are  essentially  the  outcome  of  the 
protracted  delirious  reactions  with  permanent  reduction  due 
to  permanent  damage.  They  have  been  characterized  by  the 
presence  of  memory  defects  (in  the  main  for  recent  events  and 
for  retention),  with  a  tendency  to  confabulate,  and  good 
humor  and  sense  of  well-being.  Probably  the  impulsive 
activity  noted  above  is  also  best  explained  in  terms  of  the 
organic  alteration. 

The  following  questions  submitted  to  Dr.  Hohman  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 


120  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Sachs:  Your  summary  I  think  is  excellent.  The  only  thing 
that  would  be  surprising,  I  think,  to  some  of  us,  is  the  number  of 
cases  of  euphoria  that  have  been  reported.  Outside  of  institutions 
I  doubt  whether  many  such  cases  have  been  observed.  Was  that 
a  euphoria  that  would  be  as  distinct,  for  instance,  as  the  euphoria 
of  a  general  paresis? 

Dr.  Hohman  :  I  think  rather  more  good  humor  and  cheerfulness. 

Dr.  Sachs:  It  was  not  as  distinct  as  that  of  general  paresis? 

Dr.  Hohman:  It  was  less  vacuous  but  more  real  good  humor 
and  cheerfulness.  It  stood  between  the  vacuous  and  the  empty 
euphoria  and  hypomanic  good  humor  of  the  hypomanic  state. 
The  patients  felt  fine,  like  new-born  babes  and  things  of  that  sort. 

Dr.  Barker:  Have  any  of  the  organic  type  had  the  Argyll- 
Robertson  pupil? 

Dr.  Hohman:  I  think  one  did  but  I  am  not  quite  sure. 

Dr.  Sachs:  Here  is  a  question  that  has  been  put:  Have  spinal 
punctures  been  tried  in  these  cases,  especially  in  those  that  were 
hyperactively  delirious  and  were  suffering  from  insomnia? 

Dr.  Hohman:  Yes,  repeated  lumbar  punctures  have  been  done. 
There  was  one  case  in  particular  in  which  there  was  a  reversal  of 
the  sleep  curve  and  in  addition  this  great  push  of  talk.  There  have 
been  repeated  lumbar  punctures  and  as  far  as  we  can  observe 
nothing  was  accomplished  thereby. 

Dr.  Timme:  You  mentioned  as  some  of  the  symptoms,  on  a 
vegetative  level,  thoracic  and  abdominal  hypochondriasis? 

Dr.  Hohman  :  A  great  deal  of  abdominal  pain  and  cramps  and 
pains  in  the  chest,  things  that  would  have  suggested  girdle  pains, 
and  complaint  of  things  that  might  have  passed  as  pleural  pain. 
All  of  the  physical  examinations  and  careful  sensory  examination 
revealed  nothing.  Also  endocrine  studies  were  made  and  nothing 
could  be  made  out  of  them. 

Dr.  Ladd:  You  say  that  you  place  the  deliria  in  the  organic  class 
differing  from  dementia  praecox  of  psychogenic  origin  and  state 
that  this  was  done  because  of  the  hypertonicity  not  being  present 
in  the  psychogenic  mechanism.  How  do  you  consider  the  tonicity 
in  catatonic  types  of  dementia  praecox  with  psychogenic  deliria? 

Dr.  Hohman  :  I  did  not  say  that.  I  put  the  deliria  as  organic  and 
psychogenic.  I  classify  as  organic  the  things  that  have  ordinarily 
occurred  in  the  toxic  deliria,  whereas  the  psychogenic  delirium 
is  the  hysterical  delirium  which  makes  use  of  various  disturbances 


SYMPTOMATOLOGY  121 

— as  those  things  which  arise  in  hysterical  or  other  delirious  states 
in  which  psychogenic  mechanisms  are  used. 

Dr.  Sachs:  May  I  ask  whether  in  Baltimore  you  observed  any 
improvement  in  the  chronic  forms  in  any  case  after  an  occurrence 
of  this  form? 

Dr.  Hohman:  Of  the  4  cases  which  occurred  in  the  organic 
group,  2  are  dead  and  the  other  2  are  still  in  the  same  condition. 
Unfortunately,  both  those  deaths  occurred  outside  of  the  hospital 
and  we  could  not  make  an  autopsy. 

Dr.  Hunt:  Did  all  these  cases  contain  evidence  of  some  organic 
disease  of  the  brain,  some  paralytic  infection  in  the  cranial  nerves 
or  elsewhere  in  the  early  stage? 

Dr.  Hohman:  In  one  case,  the  second  case  I  spoke  of,  there 
was  this  great  push  of  talk  for  the  first  week — nothing  except  this 
incessant  flow  of  talk  was  observed.  Later  he  developed  a  facial 
weakness,  etc.  We  have  insisted  upon  the  finding  of  two  abnormal 
things  in  the  cerebral  spinal  fluid  to  make  our  diagnosis.  That  is 
arbitrary,  but  we  did  not  include  a  lot  of  things  which  might 
have  been  regarded  as  encephalitis  unless  they  had  actual  spinal 
alterations,  cell  count  change,  change  above  ten,  or  alteration  in 
the  colloidal  gold  reaction,  etc.  Unfortunately  we  did  not  do  sugar 
studies. 

CONCLUSIONS    OF    THE    COMMISSION 

It  is  the  opinion  of  the  Commission  that  the  views  postu- 
lated in  this  section  by  Drs.  Kirby  and  Davis  and  by  Dr. 
Hohman  offer  the  correct  interpretation  of  the  psychotic 
manifestations  of  epidemic  encephalitis,  namely,  that  the 
mental  symptoms  found  are  those  which  are  in  the  main 
consistent  with  those  which  occur  in  organic  brain  disease, 
and  that  they  are  to  be  interpreted  as  directly  attributable 
to  the  disease  process. 

The  above  investigators  have  brought  out  facts  of  par- 
ticular interest  in  the  symptomatology  of  the  disease,  espe- 
cially in  respect  to  emotional  disorders  of  various  kinds, 
sleep  disturbances  and  certain  peculiarities  of  conduct. 
They  have  likewise  emphasized  that  the  symptomatology 
is  quite  unusual  at  times  and  differs  from  that  which  is  seen 
in    other    organic    brain   diseases.    All    investigators   have 


122  ACUTE  EPIDEMIC  ENCEPHALITIS 

expressed  the  opinion  that  these  symptoms  are  part  of  an 
acute  organic  psychosis  and  are  not  to  be  confused  with  other 
psychoses.  Further  clinical  observations  of  the  psychotic 
manifestations  associated  with  epidemic  encephalitis  are 
necessary  before  conclusions  are  warranted  as  to  the  ultimate 
outcome  of  these  mental  types.  The  observations  have  not 
been  over  a  period  long  enough  or  of  a  sufficient  number  of 
cases  to  warrant  a  prognosis.  It  will  be  of  interest  to  know 
whether  these  cases  eventually  recover,  whether  they  remain 
permanently  disabled,  particularly  in  emotional  spheres,  or 
whether  they  will  deteriorate.  In  view  of  the  nature  of  the 
disease,  the  possibility  of  recurrences  in  the  psychotic  states 
is  of  interest.  The  similarity  of  some  psychotic  cases  of 
epidemic  encephalitis  to  catatonic  forms  of  dementia  prsecox 
in  superficial  appearance  is  of  considerable  interest. 

The  Commission  wishes  to  refer  briefly  at  this  time  to  the 
observations  of  Drs.  Morris  Grossman  and  Junius  W. 
Stephenson  on  some  unusual  conduct  disorders  occurring  in 
children  after  attacks  of  epidemic  encephalitis.  Likewise, 
other  contributors  to  the  volume,  as  well  as  those  in  this 
chapter,  have  made  mention  of  neurasthenic  and  psychas- 
thenic sequelae.  The  changes  in  character  and  disposition  of 
children  after  having  suffered  from  this  disease  are  of 
unusual  interest;  and  the  various  tics  and  habit  spasms 
which  the  above  investigators  have  observed  after  the 
disease  in  children  are  likewise  of  great  interest.  The 
Commission  therefore  feels  that  the  mental  manifesta- 
tions associated  with  lethargic  encephalitis,  as  reported 
by  the  above  observers,  may  be  divided  into  three  large 
groups:  the  frank  psychoses,  the  psychoneuroses,  and  the 
changes  in  temperament  and  conduct  disorders.  Continued 
study  of  the  origin,  course  and  outcome  of  these  parti- 
cular mental  symptoms  in  epidemic  encephalitis  will  not 
only  throw  light  upon  the  disease  itself  but  should  also 
furnish  insight  into  the  characteristics  of  psychoses,  psy- 
choneuroses and  conduct  disorders  occurring  under  other 
circumstances. 


Chapter  V 

DIAGNOSIS,  COURSE  AND  PROGNOSIS; 
LATE   RESULTS 

THE  opinion  of  the  Commission  on  the  topics  embraced 
in  this  chapter  is  based  upon  the  investigations,  experi- 
ences and  classifications  of  the  following  contributors:  Dr. 
Lewellys  F.  Barker  of  Baltimore,  who  treated  the  subject 
of  diagnostic  criteria;  Dr.  William  B.  Cadwalader  of  Philadel- 
phia, whose  especial  investigation  was  in  the  field  of  the 
differential  diagnosis  between  epidemic  encephalitis  and 
anterior  poliomyelitis;  Dr.  Morris  Grossman  of  New  York  and 
Dr.  Junius  W.  Stephenson  of  New  York,  on  the  prognosis  in 
epidemic  encephalitis;  all  of  whom  were  especially  designated 
by  the  Association  to  cover  the  special  divisions  included  in 
this  chapter. 

Diagnostic  Criteria  in  Epidemic  Encephalitis  (Lew- 
ellys F.  Barker).  In  no  other  condition,  perhaps,  is  a 
general  diagnostic  survey,  and  especially  a  general  neurolog- 
ical and  psychiatric  survey,  more  important  for  accurate 
diagnosis  than  in  the  epidemic  encephalitis.  When,  however, 
the  symptoms  and  signs  that  are  recognizable  by  modern 
methods  have  been  accumulated,  and  when  the  sites  within 
the  nervous  system  to  which  they  point  have  been  care- 
fully determined,  there  is  now'  in  most  cases  but  little 
difficulty  in  deciding  upon  a  diagnosis  of  encephalitis  if  the 
disease  is  present. 

In  the  United  States,  initial  stages  of  various  sorts  have 
been  described.  When  the  onset  was  sudden,  there  was 
often  severe  pain  in  the  head,  fever  and  delirium,  followed 
by  a  period  of  improvement  for  a  few  days,  after  which 

123 


i24  ACUTE  EPIDEMIC  ENCEPHALITIS 

apathy,  somnolence  and  cerebral  nerve  paralyses  of  different 
sorts  or  Parkinson-like  syndromes  developed.  When  the 
onset  was  more  insidious,  the  initial  symptoms  often  con- 
sisted of  diplopia  and  slight  mental  confusion,  or,  in  some 
cases,  of  neuralgias  or  of  pareses  in  the  domain  of  one  or 
more  of  the  cerebral  nerves;  and  these  patients,  too,  often 
showed  improvement  for  a  few  days  only  to  become  somno- 
lent later.  Not  infrequently  there  was  marked  restlessness  at 
night  with  insomnia  before  a  stage  of  somnolence  was  reached. 
Of  the  abnormal  mental  symptoms  exhibited  by  encephalitic 
patients,  somnolence  or  pathological  drowsiness  is  by  far 
the  most  important  as  a  diagnostic  criterion.  The  deliria 
that  occur  in  encephalitis  are  less  characteristic  than  the 
somnolence. 

It  is  useful  from  the  standpoint  of  diagnostic  criteria  to 
adopt,  for  the  present,  the  following  dominant  clinical 
types. 

i.  The  somnolent-ophthalmoplegic  type  (febrile  or  afeb- 
rile) . 

2.  The  paralytic  (akinetic  or  hypokinetic)  type. 

3.  The  amyostatic  type  (Parkinson-like  and  cataleptic 
syndromes). 

4.  The  hyperkinetic  type  (myoclonic  forms,  choreatic 
forms,  epileptic  forms). 

5.  The  psychotic  type  (delirious  forms,  maniacal  forms, 
depressive  forms). 

6.  The  hyperalgetic  type  (painful  forms). 

7.  The  tabetic  type  (Argyll-Robertson  pupils  with  loss  of 
deep  reflexes  and,  sometimes,  with  lancinating  pains). 

8.  The  ataxic  type. 

9.  The  abortive  type  (formes  frustes;  imperfect,  rudimen- 
tary, and  ambulatory  forms). 

10.  The  aberrant  type  (intestinal  forms,  cutaneous  forms, 
vagal  forms,  etc.). 

The  occurrence  of  any  one  of  these  syndromes  at  a  time 
when  encephalitis  is  epidemic,  especially  when  it  is  associated 
with  signs  of  infection  (fever  or  leukocytosis),  should  make 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  125 

one  think  of  the  possible  existence  of  the  disease  we  are 
considering. 

The  Criteria  for  Determining  the  Sites  of  the  Lesions  in 
Epidemic  Encephalitis.  Many  of  the  syndromes  above 
mentioned  are  now  known  to  be  due  definitely  to  certain 
focal  lesions  within  the  nervous  system. 

The  somnolent  ophthalmoplegic  syndrome  points  of 
course  to  the  interbrain  and  the  midbrain  particularly. 

The  akinetic  and  hypokinetic  syndromes  (other  than 
ophthalmoplegia)  are  usually  easily  Iocalizable. 

The  amyostatic  syndromes  (including  the  Parkinson-like 
syndrome  and  cataleptic  rigidity)  are  most  interesting  as 
localizing  guides.  (Injury  to  the  corpus  striatum.) 

The  several  hyperkinetic  syndromes  may  also  be  valued 
to  a  certain  extent  for  localizing  purposes. 

The  psychotic  types  doubtless  depend  upon  diffuse 
toxic  disturbances  or  multiple  foci  of  infiltration  in  the 
telencephalon. 

Multiple  pains  of  neural  or  radicular  distribution  point  to 
a  multiple  neuritis  or  radiculitis. 

A  fair  degree  of  success  could,  from  what  has  been  said, 
be  achieved  in  the  construction  of  a  classification  based  upon 
the  different  localities  in  the  nervous  system  that  are  the 
sites  of  the  toxic-infectious  processes  in  encephalitis.  The 
term  encephalitis  would  include  (1)  all  the  inflammatory 
processes  from  the  telencephalon  to  the  mesencephalon 
inclusive  (telencephalitis,  diencephalics,  mes  encephalitis), 
these  together  making  up  cerebral  encephalitis,  and,  in  addi- 
tion, (2)  all  the  inflammations  of  the  rhombencephalon  (pons 
and  medulla  oblongata),  including  pontine  encephalitis  and 
bulbar  myelitis.  Under  the  term  myelitis  would  be  included 
all  the  inflammations  that  occur  in  the  spinal  cord  in  this 
malady  (poliomyelitis  anterior,  poliomyelitis  posterior,  mye- 
litis transverse,  and  myelitis  funicularis.  Under  neuritis 
could  be  included  the  inflammations  that  occur  in  the  extra- 
central  portions  of  the  cerebral  and  spinal  nerves  (radiculitis, 
peripheral    neuritis).    Under    meningitis,    or    rather    lepto- 


126  ACUTE  EPIDEMIC  ENCEPHALITIS 

meningitis,  would  be  included  patchy  inflammations  of  the 
soft  meninges.  Various  combinations  of  these  different  local 
inflammations  are  met  with  in  a  single  case.  In  some  instances 
it  would  seem  legitimate  to  speak  even  of  a  meningo-enceph- 
alo-my  elo-neuritis . 

Differential  Diagnosis  of  Epidemic  Encephalitis.  The 
neurological  and  psychiatric  data  having  been  collected,  the 
co-existence  of  symptoms  and  signs  constituting  one  or  more 
of  the  type  syndromes  having  been  recognized,  and  the 
consideration  of  the  clinical  findings  for  their  Iocalizatory 
significance  having  been  completed,  sufficient  evidence  is 
as  a  rule  at  hand  to  permit  one  to  decide  whether  the 
patient  under  study  is  or  is  not  suffering  from  epidemic 
encephalitis. 

Caution  is  always  advisable,  however,  before  permitting 
one's  self  to  arrive  at  a  definite  diagnostic  conclusion.  For 
epidemic  encephalitis  may  mimic  very  closely  any  one  of  a 
whole  series  of  neurological  and  psychiatric  -conditions  of 
another  nature;  and  the  reverse  is  of  course  also  true — these 
conditions  may  wear  the  guise  of  one  or  another  form  of 
epidemic  encephalitis. 

In  the  first  outbreaks  of  epidemic  encephalitis  in  Europe, 
"botulism,"  meningitis,,,  and  the  " Heine-Medin  disease" 
were  the  erroneous  diagnoses  most  often  made.  In  the 
Winnipeg  epidemic  (19 19),  cases  that  were  diagnosed  clini- 
cally as  "cerebral  hemorrhage,"  "uremia"  and  "tuberculous 
meningitis"  were  found  at  autopsy  to  have  been  cases  of 
encephalitis  (William  Boyd). 

Among  the  infectious  processes  with  which  epidemic 
encephalitis  is  likely  to  be  confused,  the  following  stand  out 
prominently:  (1)  meningitis,  (2)  influenza  and  grippe  infec- 
tions, (3)  the  Heine-Medin  disease  and  (4)  multiple  neuritis, 
especially  the  infectious  form.  Confusion  may  also  occur, 
though  less  frequently,  with  (5)  typhoid  fever,  (6)  mumps, 
(7)  infectious  arthritis  or  myositis,  (8)  tetanus,  or  (9)  hydro- 
phobia. Here,  too,  should  be  considered  the  differentiation 
(10)  from  forms  of  encephalitis,  myelitis  or  encephalomye- 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  127 

litis  other  than  those  due  to  the  specific  virus  that  must  be 
responsible  for  the  present  epidemic. 

Among  the  intoxications  which  may  closely  resemble 
epidemic  encephalitis  with  somnolence  may  be  mentioned 
(1)  uremia,  (2)  acidosis,  (3)  cholemia,  (4)  drug-intoxications 
(veronal  poisoning,  cocaine  poisoning,  alcoholic  intoxication, 
etc.),  and  (5)  botulism. 

The  vascular  lesions  most  likely  to  give  rise  to  states  that 
may  be  confused  with  epidemic  encephalitis  are:  (1)  cerebral 
hemorrhage;  (2)  cerebral  thrombosis;  (3)  cerebral  embolism; 
(4)  sinus  thrombosis,  and  (5)  cerebral  atherosclerosis. 

Cerebrospinal  lues,  dementia  paralytica  and  tabes  dorsalis 
are  sometimes  believed  to  exist  when  the  patient's  state  is 
really  due  to  epidemic  encephalitis. 

Epidemic  encephalitis  may  occasionally  give  rise  to 
clinical  pictures  that  make  one  think  of  cerebral  tumor, 
cerebellar  tumor,  pontile  tumor,  or  tumor  of  the  cerebello- 
pontile  angle. 

Myoclonias.  During  the  past  two  years  myoclonic 
forms  of  epidemic  encephalitis  have  been  frequently 
observed. 

Chorea.  Many  choreiform  manifestations  have  been  met 
with  since  the  hyperkinetic  forms  of  epidemic  encepha- 
litis have  been  prevalent. 

Parkinson s  Disease.  Parkinson-like  syndromes,  espe- 
cially paralysis  agitans  sine  agitatione  with  pyramidal 
tract  symptoms  have  been  frequently  met  with  among  the 
encephalitic  cases  in  all  countries  in  which  the  epidemic 
disease  has  been  fully  described.  The  acute  development 
of  this  amyostatic  syndrome  (rigidity,  characteristic  atti- 
tudes, facial  mask,  and  poverty  of  movement  with  or  without 
tremor)  and  the  surprising  disappearance  of  the  phenomena, 
in  many  instances  in  the  course  of  a  few  weeks,  have  been 
striking  features  of  this  type  of  encephalitis. 

Cataleptic  or  Catatonic  States.  In  the  first  English  epi- 
demic/many  of  the  cases  of  encephalitis  were  described  under 
the   name   of   "epidemic   stupor"    and   in   other   countries 


128  ACUTE  EPIDEMIC  ENCEPHALITIS 

cataleptic  states,  catatonic  states  and  waxy  flexibility  have 
been  described  as  a  part  of  the  symptomatology  of  many 
cases  of  epidemic  encephalitis. 

Myasthenia  Gravis.  Several  of  the  patients  suffering  from 
encephalitis  in  this  epidemic  have  at  first  been  thought  to  be 
suffering  from  myasthenia  gravis,  owing  to  certain  manifes- 
tations (profound  asthenia;  general  muscular  weakness;  and, 
especially,  weakness  of  muscles  innervated  by  the  motor 
cerebral  nerves,  exhibited  as  ptosis,  facial  paralysis,  dys- 
masesia,  dysarthria  and  dysphagia). 

Progressive  Central  Muscular  Atrophy.  Either  the  spinal 
or  the  bulbar  form  of  progressive  (central)  muscular  atrophy 
may  sometimes  be  simulated  by  the  more  subacute  forms 
of  epidemic  encephalitis. 

Hysteria  and  Neurasthenia.  Some  of  the  more  obscure 
forms  of  epidemic  encephalitis  have  been  erroneously 
supposed  to  be  cases  of  hysteria  or  of  neurasthenia.  The 
pathological  drowsiness  of  encephalitis  may  be  confused  with 
hysterical  twilight  states  or  hysterical  narcolepsy.  The 
residual  neuralgias,  the  restlessness,  the  insomnia  and  the 
disturbed  mentality  of  the  convalescent  encephalitic  may  be 
ascribed  to  neurasthenia  or  to  psychasthenia. 

CONCLUSIONS 

On  account  of  the  toxic  component  and  of  the  inflamma- 
tory infiltrative  component  of  the  disease-process,  both 
general  and  widely  disseminated  focal  manifestations  of 
involvement  of  the  central  and  peripheral  nervous  systems 
may  occur  in  encephalitis  and  give  rise  to  the  most  diverse 
disturbances  of  motility,  of  sensation,  of  coordination,  of  the 
reflexes  and  of  the  psyche. 

Despite  the  enormous  number  of  clinical  forms  met  with 
in  epidemic  encephalitis,  there  is  a  marked  tendency  to  the 
repetition  of  certain  characteristic  forms  or  types,  of  which 
the  somnolent-ophthalmoplegic,  the  paralytic,  the  amyo- 
static  and  the  hyperkinetic  are  the  commonest. 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  129 

When  the  disease  is  epidemic  it  can  usually,  in  outspoken 
cases  at  least,  despite  the  clinical  diversity,  be  easily  recog- 
nized, though  in  abortive,  imperfect,  rudimentary  and 
aberrant  cases,  great  difficulties  in  diagnosis  may  be 
experienced  and  doubtless  many  cases  remain  entirely 
unrecognized. 

The  occurrence  in  a  patient  of  (a)  pathological  drowsiness 
(lethargy),  (6)  cerebral  nerve  paralysis  (especially  ophthal- 
moplegia), (c)  an  acutely  developing  Parkinsonian  syn- 
drome, (d)  a  cataleptic  or  a  catatonic  state,  (e)  a  myoclonia, 
(/)  a  chorea,  (g)  pupillary  disturbances,  (h)  violent  neuralgia, 
(j)  a  poliomyelitic  syndrome,  (/)  a  peculiar  delirium,  (k)  sl 
psychotic  state,  or  (/)  signs  of  meningeal  irritation  in  times 
when  encephalitis  is  epidemic  should  make  one  think  of  the 
possible  existence  of  the  disease. 

Though  epidemic  encephalitis  may  simulate  any  one  of  a 
large  number  of  neurological  and  psychiatric  syndromes  of 
entirely  different  origin,  the  mode  of  onset,  the  course,  and 
the  results  of  carefully  conducted  neurological  and  psychia- 
tric examinations  (including  an  examination  of  the  cerebro- 
spinal fluid)  will  usually  yield  the  diagnostic  criteria  that 
suffice  for  its  recognition  and  differentiation. 

The  following  questions  submitted  to  Dr.  Barker  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Timme  :  Dr.  Bailey  has  sent  in  a  list  of  four  or  five  questions 
which  I  will  ask  the  secretary  to  read  for  the  bringing  out  of 
some  of  the  prominent  points. 

Dr.  Kennedy:  What  are  the  characteristics  of  amnesia  and 
memory  disturbances? 

Dr.  Barker:  In  the  cases  that  I  have  seen  there  is  frequently 
loss  of  memory  for  the  events  that  occurred  at  the  time  of  the 
onset  of  the  drowsiness.  I  remember  one  patient  made  a  long 
automobile  trip  and  was  awake  part  of  the  time  and  asleep  part 
of  the  time,  and  lost  all  memory  afterward  of  what  had  occurred 
during  that  trip.  A  second  feature  has  been  the  Korsakoff  type 
9 


i3o  ACUTE  EPIDEMIC  ENCEPHALITIS 

of  memory  disturbance  where  there  was  disorientation  for  time, 
place  and  persons,  and  pseudo-reminiscences,  confabulation,  and 
the  third  type  of  memory  disturbance  was  more  like  that  seen  in 
dementia  paralytica,  or  in  some  ot  the  forms  of  cerebral  atherosis 
with  especially  loss  of  memory  for  recent  events,  diminution  of  the 
recording  faculty,  with  fair  preservation  of  the  older  memories. 

Dr.  Kennedy:  What  is  the  average  duration  of  such  prodro- 
mata  as  headache,  sore  throat,  general  weakness,  etc.,  before 
definite  symptoms  of  the  disease  become  present? 

Dr.  Barker:  In  my  own  cases  it  has  been  hard  to  determine 
that.  I^have  seen  them  as  a  rule  in  the  latter  stages,  and  it  was 
hard  to  get  an  accurate  history,  but  it  seems  to  vary  a  great  deal. 
There  were  some  in  which  the  prodromata  lasted  only  a  short  time; 
others  in  which  there  had  been  complaints  over  quite  a  long  period, 
and  that  seems  to  be  in  accord  with  the  reports  in  the  bibliography. 

Dr.  Kennedy:  Does  the  reaction  to  the  infection  show  any 
variations  in  different  races  or  in  predisposed  individuals?  And 
that  raises  another  question,  Has  any  predisposition  been 
demonstrated? 

Dr.  Barker:  Reactions  are  so  different  in  the  different  epi- 
demics; I  think  that  those  differences  are  more  outstanding  than 
racial  differences.  If  one  studies,  for  instance,  an  account  of  the 
two  epidemics  in  Austria  and  the  recent  epidemic  in  Italy,  and 
the  epidemics  in  Germany,  in  France  and  in  this  country,  one  will 
see  that  there  are  very  great  differences  in  the  clinical  picture  in 
successive  epidemics  in  the  same  country,  and  the  same  kinds  of 
pictures  have  come  out  in  all  the  countries  if  one  studies  the 
bibliography  carefully.  As  to  predisposition,  the  literature  is 
pervaded  with  histories  of  influenza  before  the  attack,  although 
large  numbers  of  the  cases  have  no  preceding  history  of  influenza, 
and  there  are  many  who  think  that  the  so-called  influenza  was 
really  this  disease  at  the  beginning  rather  than  an  ordinary  in- 
fluenza. The  only  other  predisposing  factor  that  I  have  seen 
is  alcoholism.  I  have  seen  several  alcoholic  cases  that  developed 
encephalitis,  but  they  are  not  specially  numerous  considering  the 
total  number  of  cases  seen.  I  think  I  was  impressed  by  that  because 
I  was  on  the  lookout  for  alcoholics  especially. 

Dr.  Kennedy:  What  percentage  of  cases  run  their  course 
without  mental  symptoms? 

Dr.  Barker:  It  would  depend  on  how  you  define  a  mental 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  131 

symptom.  If  you  include  pain  and  drowsiness  as  mental  symptoms, 
I  think  the  percentage  would  be  very  small,  but  if  you  mean  with- 
out deliriums  or  psychotic  states,  I  think  there  is  a  large  percentage. 
That  is  an  impression  without  any  definite  figures. 

Dr.  Kennedy:  The  last  question — What  post-mortem  verifi- 
cations are  there  for  various  localized  symptoms  mentioned? 

Dr.  Barker:  I  have  none  of  my  own;  I  have  no  autopsy.  There 
have  been  some  at  the  hospital.  In  the  literature  there  is  a  growing 
body  of  material  with  confirmation  of  the  present  existent  know- 
ledge upon  the  relation  of  clinical  syndromes  to  sites  of  lesions. 
I  think  almost  all  that  we  know  and  say  about  the  localization 
of  lesions  at  present  is  based  upon  our  general  knowledge  of 
neurological  localizing  diagnosis,  and  where  a  confirmation  has 
been  possible  it  has  been  made.  There  has  been  a  good  deal  of 
confirmation  especially  of  the  bulbar  and  other  lesions,  and  in  the 
poliomyelitic  syndromes  they  have  been  verified  at  autopsy  in  a 
good  many  cases. 

Dr.  Prince:  May  not  acute  idiopathic  internal  hydrocephalus 
(Quincke)  simulate  the  ophthalmoplegic  type,  and  how  would  you 
differentiate  this  condition? 

Dr.  Barker:  Yes,  I  think  it  could  simulate  it.  As  I  recall,  it 
is  a  febrile  Quincke.  It  might  be  very  difficult  to  differentiate. 
I  think  you  would  be  much  more  likely  to  suspect  encephalitis  than 
that  condition  on  account  of  its  rarity  in  times  of  epidemic. 

Dr.  Prince:  I  note  that  it  has  not  been  mentioned  at  all  in  the 
discussion,  and  I  think  it  has  the  same  ophthalmoplegia  as  the 
headache,  etc.,  but  the  symptoms  are  variable.  I  have  seen  three 
cases.  It  seems  to  me  it  might  be  very  difficult  at  times  to 
differentiate. 

Dr.  Barker:  Would  lumbar  puncture  show  any  differences? 
If  there  was  an  increased  cell  count,  positive  globulin,  that  would 
favor  encephalitis,  but  half  the  cases  of  encephalitis  have  a  negative 
fluid.  Is  it  quite  certain  that  the  Quincke  syndrome  is  not  an 
encephalitis?  (Laughter) 

Dr.  Prince:  Merely  in  the  autopsies  there  have  been  found 
no  inflammatory  conditions  at  all  at  the  base  of  the  brain  or  any 
part  of  the  brain,  in  fact;  even  of  the  choroid  plexus,  etc.,  no 
inflammatory  conditions  were  found.  I  do  not  know  of  any  exam- 
ination that  has  been  made  of  recent  years,  but  microscopically 
nothing  has  been  found. 


i32  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Patrick:  I  have  a  question  by  Dr.  Davis:  If  in  general 
paresis  there  is  not  a  toxemia  but  a  syndrome  based  on  anatomical 
localization  of  spirochete,  have  we  any  reason  to  think  epidemic 
encephalitis  not  a  toxemia  but  instead  entirely  dependent  on 
anatomical  localized  growths  of  the  encephalitis  virus? 

Dr.  Barker  :  My  answer  to  that  would  be  entirely  speculative. 
In  the  first  place,  I  am  not  quite  convinced  that  the  whole  picture 
of  dementia  paralytica  is  devoid  of  intoxicating  element.  We  know 
there  is  an  inflammatory  element,  due  to  localization,  but  there 
may  also  be  a  chronic  intoxication.  There  is  a  good  deal  of  evi- 
dence, I  think,  especially  since  von  Economo's  last  paper,  of  a 
marked  toxic  element  at  the  beginning  of  this  disease  of  epidemic 
encephalitis  which  is  apparently  responsible  for  the  diffused 
processes  in  the  very  early  stage  of  the  disease,  and  the  inflamma- 
tory infiltrative  changes  which  occur  apparently  only  later.  It  does 
seem  as  though  epidemic  encephalitis  had  both  a  toxic  component 
as  well  as  an  inflammatory  infiltrative  component,  and  the  evidence 
is  in  the  internal  organs.  Von  Economo  has  had  made  in  a  labora- 
tory in  Vienna  a  number  of  metabolical  studies,  blood  chemistry 
and  urinal  function  studies,  very  suggestive  of  a  toxic  process  as 
well  as  of  an  inflammatory  infiltrative  process. 

Dr.  Taylor:  You  spoke  of  the  cataleptic  type;  to  what  extent 
have  you  observed  that  cataleptic  manifestation,  or  how  cataleptic 
was  it? 

Dr.  Barker:  I  have  used  the  term  cataleptic  as  synonymous 
with  catatonic  rigidity.  I  have  seen  two  cases  that  would  be  looked 
upon  easily  as  catatonic  stupor,  where  the  patient  lay  like  an 
image  on  the  bed — immobile,  apathetic,  making  no  movement, 
hardly  answering  questions,  not  taking  food,  not  speaking,  marked 
poverty  of  movement,  very  much  like  what  is  ordinarily  described 
as  a  catatonic  state,  and  I  think  that  in  the  English  epidemic  a 
large  number  of  the  cases  described  as  epidemic  stupor  seemed  to 
have  been  of  that  type.  Nonne  has  described  them  in  the  Ham- 
burg epidemic  as  quite  common — this  image-like,  rigid,  immobile 
type,  without  quite  the  Parkinsonian  mask  but  with  almost  waxy 
flexibility. 

Dr.  Taylor:  I  should  like  to  know  whether  this  cataleptic 
type  was  to  the  extent  of  the  patient  preserving  any  position 
which  one  would  give  him. 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  133 

Dr.  Barker:  Some  of  them  have  definitely  held  a  passive  posi- 
tion given  to  the  limbs. 

Dr.  Brown:  Have  you  seen  prolonged  neurasthenic  or  psychas- 
thenic states  following  lethargic  encephalitis? 

Dr.  Barker:  Yes. 

Dr.  Freeman  :  Has  paralysis  of  associated  lateral  movements  of 
the  eyeballs  been  observed  in  epidemic  encephalitis? 

Dr.  Barker:  Yes.  It  is  not  common,  but  it  has  been  observed. 

Dr.  Dana:  Have  you  observed  the  phenomenon  that  Dr. 
Abrahamson  speaks  of — that  all  cases  of  this  encephalitis  were 
ushered  in  by  some  mucous  membrane  irritation?  He  speaks  of 
that  as  being  uniformly  the  case.  It  has  been  overlooked  by  most 
observers,  but  if  observations  are  carefully  made  you  will  find 
that  a  patient  has  a  pharyngeal  irritation  or  nasal  irritation,  or 
oral  or  bronchial  or  intestinal,  that  precedes  the  disease. 

Dr.  Barker:  I  have  seen  relatively  few  cases  at  the  very  begin- 
ning myself.  I  had  not  been  especially  impressed  with  that  point, 
though  a  history  of  nasal  pharyngitis  is  not  uncommon  in  the  litera- 
ture preceding  cases,  and  there  is  one  group  of  cases  described 
as  an  aberrant  form  in  which  intestinal  symptoms  have  been 
pronounced.  I  have  seen  one  or  two  that  developed  intestinal 
symptoms  during  the  course,  but  I  have  not  been  especially  im- 
pressed with  mucous  membrane  inflammations  as  an  antecedent. 

Special  Distinction  Between  Epidemic  Encephalitis 
and  Poliomyelitis  (William  B.  Cadwalader).  In  consid- 
ering the  relation  between  epidemic  (lethargic)  encephalitis 
and  acute  anterior  poliomyelitis,  much  depends  upon  whether 
the  subject  is  studied  from  the  purely  clinical  aspect,  or  from 
exact  comparisons  made  with  post-mortem  material.  In 
each  disease,  however,  careful  examinations  by  both  methods 
should  be  made  before  conclusions  are  drawn. 

It  is  a  firmly  established  fact  that  several  types  of  exuda- 
tive inflammations  of  the  brain  are  infectious  in  character. 
It  is  not  possible,  however,  from  microscopic  examinations  of 
tissues  alone,  to  separate  with  precision  the  alterations 
produced  in  the  nervous  system  by  each  of  the  different 
known  agents.  True,  certain  individual  cases  have  been 
recorded  from  time  to  time  in  which  characteristic  differences 


i34  ACUTE  EPIDEMIC  ENCEPHALITIS 

seem  to  be  present,  but  when  these  points  are  analyzed  care- 
fully, it  canjgenerally  be  shown  that  they  are  based  chiefly 
upon  the  situation  of  the  lesions,  or  are  apparent  variations 
caused  by  modifications  in  the  intensity  and  duration  of  the 
disease.  They  cannot,  therefore,  be  regarded  as  characteristi- 
cally different  tissue  reactions  corresponding  strictly  and 
precisely  to  various  infectious  agents. 

This  opinion  has  frequently  been  expressed  by  different 
authors,  and  especially  in  regard  to  the  practical  impossi- 
bility of  separating  the  lesions  of  acute  anterior  poliomyelitis 
from  those  of  epidemic  (lethargic)  encephalitis  when  exam- 
ined under  the  microscope. 

It  is  not  surprising,  therefore,  that  the  clinical  differentia- 
tion may  also  be  quite  impossible. 

Like  the  onset  of  acute  anterior  poliomyelitis,  that  of 
epidemic  (lethargic)  encephalitis  is  an  exceedingly  irregular 
one.  From  the  studies  made  during  epidemics  by  Wickman 
and  others  we  learn  that  an  abortive  type  of  poliomyelitis  in 
which  paralysis  is  absent  is  frequently  encountered,  and  thus 
our  present  conception,  that  acute  anterior  poliomyelitis  is 
an  infectious  systemic  disease  in  which  paralysis  may  or 
may  not  occur,  has  become  established.  The  number  of  cases 
of  acute  anterior  poliomyelitis  in  which  paralysis  is  absent 
varies  considerably  in  different  epidemics,  but  most  observers 
agree  that  the  abortive  types  represent  about  50  per  cent  of 
all  cases  of  the  disease. 

Comparing  the  onset  and  development  of  epidemic  (lethar- 
gic) encephalitis,  almost  all  recent  observations  show  that  the 
condition  is  dependent  upon  a  previous  attack  of  influenza. 
Epidemic  (lethargic)  encephalitis  is  not,  as  a  rule,  a  part  of 
an  attack  of  typical  influenza,  but  it  is  a  well-known  fact 
that  epidemic  (lethargic)  encephalitis  may  follow  an  attack 
of  influenza.  For  this  reason,  premonitory  symptoms,  or 
those  preceding  the  development  of  paralysis  in  epidemic 
(lethargic)  encephalitis,  may  be  the  same  as  those  of  infec- 
tion, or  merely  incidents  in  the  convalescence  from  that 
disease.  This  stage  of  the  disease,  therefore,  in  which  the 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  135 

symptoms  resemble  those  of  a  chronic  influenzal  infection, 

represents   the   general   systemic   phase,    which   is    exactly 

analogous  to  the  abortive  or  non-paralytic  types  of  acute 

anterior  poliomyelitis.  It  may,  however,  progress  and  become 

a  specialized  expression  in  the  form  of  an  affection  of  the 

central  nervous  system  with  paralysis.  In  this  respect  the 

diseases  are  closely  similar,  and  it  seems  unnecessary  to 

quote  here  the  details  of  cases  showing  no  paralysis.  For 

present  purposes  it  is  quite  sufficient  to  refer  to  the  fact 

that   the   differentiation    of   non-paralytic    cases    of   acute 

anterior  poliomyelitis,  and  of  non-paralytic  cases  in  which 

influenzal  infection  of  the  nervous  system  is  suspected,  is 

dependent  largely  upon  the  knowledge  of  the  occurrence  of 

an  epidemic  of  acute  anterior  poliomyelitis  or  the  prevalence 

of  influenza  or  of  epidemic  (lethargic)   encephalitis  in  the 

community  in  which  the  cases  are  observed. 

_  Considered  topographically,  there  are  certain  well-recog- 
nized  forms  of  acute  anterior  poliomyelitis  in  which  the  in- 
flammatory process  is  well  localized  and  reaches  its  greatest 
intensity  in  the  cerebral  peduncles,  pons,  or  medulla  oblon- 
gata, the  spinal  cord  and  cerebral  hemispheres  being 
unaffected.  These  are  the  cases  that  show  the  strongest 
resemblance  to  epidemic  (lethargic)  encephalitis.  The  weight 
of  opinion,  moreover,  strongly  favors  the  view  that  the  polio- 
encephalitis superior  and  inferior  or  the  polioencephalo- 
myelitis  of  Wernicke  is  true  influenzal  encephalitis,  and 
merely  modifications  in  type  of  the  same  disease. 

Epidemic  poliomyelitis  is  generally  believed  to  occur 
during  the  hot  weather,  particularly  in  July  and  August. 
Most  of  the  victims  are  children,  and  the  lower  motor  neuron 
type  of  paralysis  is  that  most  frequently  encountered  in 
cases  with  paralysis.  The  onset  is  sudden.  Epidemic 
(lethargic)  encephalitis  is  believed  to  occur  chiefly  during 
the  winter  months,  the  majority  of  cases  having  been  met 
in  adults.  Not  rarely  a  greater  number  of  cases  are  seen 
in  which  only  the  cranial  nerves  are  affected,  and  there  is 
prolonged  lethargy,  which  is  rare  in  acute  anterior  poliomye- 


136  ACUTE  EPIDEMIC  ENCEPHALITIS 

litis.  While  such  tendencies  are  important,  they  are  of  no 
value  in  determining  the  nature  of  the  disease  in  a  given  case. 

Lethargy  is  not  always  present  in  cases  of  epidemic  (lethar- 
gic) encephalitis;  moreover,  it  occasionally  occurs  with 
acute  anterior  poliomyelitis.  Lethargy  in  various  degrees, 
stupor,  or  somnolence,  frequently  with  delirium,  may  occur 
from  intoxication  in  many  different  infectious  processes, 
and  while  very  common  in  epidemic  (lethargic)  encephalitis, 
it  is  not  in  itself  characteristic  of  the  disease. 

The  clinical  manifestations  exhibited  by  lesions  in  the 
mid-brain  are  most  varied.  Any  extensive  lesion  in  the 
bulb  is  almost  invariably  rapidly  fatal,  but  the  acute  symp- 
toms in  both  acute  anterior  poliomyelitis  when  it  affects 
the  bulb,  as  well  as  in  epidemic  (lethargic)  encephalitis,  may 
be  severe.  Nevertheless,  they  will  often  clear  up,  leaving  a 
paralysis  limited  to  one  or  more  cranial  nerves.  In  acute 
anterior  poliomyelitis  the  seventh  or  facial  nerve  is  said  to 
be  most  frequently  affected,  whereas  the  third  nerve  is  most 
often  affected  in  epidemic  (lethargic)  encephalitis,  and  also 
in  Wernicke's  polioencephalitis.  Diplopia  is,  therefore,  an 
early  sign.  However,  any  of  the  cranial  nerves,  as  well  as  the 
limbs,  may  be  paralyzed  in  each  of  these  diseases,  from  in- 
volvement of  the  pyramidal  tracts  from  within  the  bulb. 
Neither  the  character  of  the  paralysis  of  the  individual  cran- 
ial nerves  nor  combinations  of  types,  such  as  unilateral, 
bilateral,  or  multiple  or  single,  have  any  significance  in 
determining  the  etiology.  These  phenomena  merely  furnish 
indications  of  the  locality  of  the  inflammation,  and  the  direc- 
tion and  extent  of  its  distribution. 

Cases  of  so-called  influenzal  myelitis  have  been  observed 
from  time  to  time. 

A  somewhat  rare  manifestation  of  acute  anterior  polio- 
myelitis is  a  transverse  lesion  of  the  spinal  cord,  the  patient 
exhibiting  complete  flaccid  paralysis  of  both  legs,  loss  of 
sphincter  control,  and  absence  of  sensation  up  to  the  level 
of  the  lesion.  The  latter  may  remain  complete  or  may  clear 
up,  leaving  the  patient  with  spastic   paraplegia  with  in- 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  137 

creased  knee-jerk,  defective  control  of  the  bladder,  etc.  It 
must  be  admitted  that  positive  proof  that  such  cases  are 
caused  by  the  virus  of  acute  anterior  poliomyelitis  is  lacking, 
yet  Batten  (Brain,  191 6,  xxxix,  1  and  2)  observed  such 
cases  during  an  epidemic  of  acute  anterior  poliomyelitis. 
B.  Sachs  (J.  Nerv.  &  Merit.  Dis.,  19 12,  xxxix,  p.  757)  re- 
corded a  case  of  acute  anterior  poliomyelitis  in  a  girl  aged 
eighteen,  with  sudden  onset  of  complete  flaccid  paralysis  and 
loss  of  sensation  up  to  the  xiphoid  cartilage,  with  complete 
recovery  in  two  months.  The  cerebrospinal  fluid  showed  a 
high  lymphocytic  count. 

Netter  and  Levaditi  (Bull,  et  mem.  Soc.  med.  d.  hop.  de 
Par.,  1914,  Ser.  3,  xxxvii,  570)  reported  4  cases  presenting 
symptoms  of  transverse  myelitis  which  they  attribute  to  the 
virus  of  acute  anterior  poliomyelitis.  These  authors  were 
able  to  show  that  the  blood  of  a  patient  who  had  recovered, 
possessed  the  property  of  neutralizing  the  virus  of  acute 
anterior  poliomyelitis. 

The  writer  recently  observed  a  similar  case  in  an  adult,  in 
whom  there  was  a  history  of  an  attack  of  influenza  one  year 
prior  to  the  onset,  and  a  chronic  cough  and  pharyngitis  that 
had  persisted  until  within  a  few  months  preceding  the  onset 
of  the  present  condition. 

In  cases  of  epidemic  (lethargic)  encephalitis  the  spinal 
cord  is  not,  as  a  rule,  believed  to  be  affected.  In  acute  anterior 
poliomyelitis  the  spinal  cord  is  involved  much  more  fre- 
quently than  other  portions  of  the  nervous  system.  At  a 
meeting  of  the  Philadelphia  Neurological  Society,  held  in 
November,  1920,  Winckleman  and  Weisenburg  reported  a 
very  important  case  of  epidemic  (lethargic)  encephalitis 
which  they  had  observed  clinically  and  at  post  mortem,  and 
had  found  the  usual  evidences  of  that  disease  in  the  basal 
ganglia,  reaching  the  greatest  intensity  in  the  pons  and 
medulla  oblongata.  They  also  found  intense  perivascular 
infiltration  and  edema.  limited  to  the  gray  matter  of  the 
cervical  and  upper  thoracic  portions  of  the  spinal  cord. 
These  alterations  were  identical  in  character  and  in  location 


138  ACUTE  EPIDEMIC  ENCEPHALITIS 

to  those  usually  found  in  cases  of  acute  anterior  poliomye- 
litis, thus  proving  conclusively  that  in  epidemic  (lethargic) 
encephalitis  the  spinal  cord  may  be  affected. 

A  closely  similar  case  is  that  reported  by  Harbitz  (Norsk. 
Mag.  j.  Laegevidensk.,  Kristiania,  January,  1920.) 

Local  muscular  atrophy  is  the  one  outstanding  symptom  of 
acute  anterior  poliomyelitis  not  observed  in  epidemic 
(lethargic)  encephalitis,  yet  Grinker  (J.  Nerv.  and  Merit. 
Dis.,  October,  1920,  hi,  No.  4,  323)  refers  to  a  curious  case 
that  he  regards  as  a  combination  of  acute  anterior  poliomye- 
litis and  epidemic  (lethargic)  encephalitis.  One  year  after 
having  influenza  the  patient  had  an  attack  resembling 
apoplexy,  with  left-sided  spastic  hemiplegia.  At  first  there 
were  high  leukocytosis  and  fever,  transient  sixth  nerve  palsy 
and  strabismus,  hyperemia  of  the  optic  nerves,  and  muscular 
atrophy  of  the  face  and  upper  limb.  Ten  days  later  peripheral 
facial  palsy  followed  the  cerebral  paralysis,  and  there  was 
atrophy  of  the  muscles  of  the  forearm  and  hand.  The  left 
thenar  and  hypothenar  eminences  resembled  the  Aran- 
Duchenne  type  of  atrophy.  Improvement  occurred. 

These  observations  tend  to  show  that  in  epidemic  (lethar- 
gic) encephalitis  the  extent  of  the  inflammatory  process  is 
exceedingly  variable,  and  that  the  spinal  cord  may  be 
affected.  Spinal  symptoms  associated  with  bulbar  signs  do 
not,  therefore,  afford  sufficient  evidence  on  which  to  elimi- 
nate the  possibility  of  epidemic  (lethargic)  encephalitis  in 
diagnosis,  without  consideration  of  the  associated  factors; 
neither  does  the  absence  of  spinal  cord  involvement  lessen 
the  probability  of  the  bulbar  symptoms  being  due  to  the 
virus  of  acute  anterior  poliomyelitis. 

In  concluding,  the  opinion  is  adduced  that  epidemic 
(lethargic)  encephalitis  is  an  infectious  disease,  having  a 
separate  and  distinct  entity  that  is  not  to  be  confused  with 
acute  anterior  poliomyelitis,  from  which  it  differs  particu- 
larly in  the  long  survival  of  the  virus  in  the  central  nervous 
system.  Its  course  may,  therefore,  be  very  irregular,  and  be 
attended  with  remissions  and  exacerbations  extending  over 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  139 

months  or  years.  The  differential  diagnosis  between  acute 
anterior  poliomyelitis  and  epidemic  (lethargic)  encephalitis 
will  often  be  impossible  to  make  if  only  the  subjective  and 
objective  signs  are  considered.  Much  will  depend  upon  the 
knowledge  of  existing  epidemics  and  the  weighing  of  cir- 
cumstantial evidence  afforded  by  the  associated  phenomena 
at  the  onset  of  the  illness  as  well  as  before  it  develops. 

Prognosis  and  Late  Results  (Morris  Grossman). 
There  have  been  about  145  cases  of  epidemic  encephalitis  on 
the  Neurological  and  Medical  Services  at  Mt.  Sinai  Hospital 
during  the  epidemics  of  this  disease  during  19 19  and  1920. 
A  great  many  of  these  patients  left  the  hospital  soon  after 
the  acute  infection  had  subsided,  showing  some  residual 
symptoms  and  signs  of  the  disease.  After  a  number  of  months 
had  elapsed,  we  felt  that  it  would  be  of  interest  to  reexamine 
these  patients  in  order  to  determine,  what,  if  any  changes  were 
still  present.  With  this  object  in  view,  this  follow-up  study 
was  undertaken.  Altogether  89  patients  were  reexamined. 

In  order  to  be  reasonably  certain  that  none  of  the  symp- 
toms or  residual  signs  found  at  this  reexamination  was  still 
part  of  the  acute  stage  of  the  disease,  at  least  six  months  were 
allowed  to  elapse  before  a  patient  was  reexamined.  The 
earliest  cases  were  seen  late  in  19 18,  so  that  some  of  the 
patients  were  examined  approximately  two  years  after  their 
acute  illness.  A  complete  neurological  examination  was  made 
in  each  case. 

No  attempt  will  be  made  to  correlate  the  symptoms  and 
physical  findings  in  this  reexamination  with  those  noted 
during  the  acute  stage  of  the  illness. 

The  findings  in  the  cases  may  be  grouped  under  the  follow- 
ing headings:  (i)JPsychic  disturbances;  (2)  tremor  and 
irregular  involuntary  movements;  (3)  disturbance  in  attitude 
and  gait;  (4)  disturbance  in  tonus  and  reflexes;  (5)  residual 
symptoms  in  cranial  nerves;  (6)  pupillary  disturbances; 
(7)  epilepsy;  (8)  other  residual  symptoms  and  signs;  (9) 
progressive  cases;  (10)  mortality  in  these  145  cases. 


i4o  ACUTE  EPIDEMIC  ENCEPHALITIS 

Psychic  Disturbances.  Fifty-one  of  the  89  cases  studied 
showed  derangement  in  their  psychic  functions  in  one  form 
or  another,  and  26  of  these  51  cases  complained  of  various 
degrees  of  irritability.  In  6  of  these,  the  patients  had  become 
so  irritable  since  their  illness  that  they  quarreled  constantly 
with  everybody  who  came  in  contact  with  them.  A  number 
stated  that  they  had  no  desire  to  associate  with  anyone,  but 
preferred  to  be  alone.  They  complained  of  restlessness.  They 
were  easily  disturbed  and  would  be  startled  and  frightened 
at  the  slightest  noise.  They  complained  of  being  unable  to 
concentrate  their  minds  on  any  subject,  and  lacked  interest 
in  current  events.  Their  mental  reactions  were  retarded  and 
they  were  slow  in  following  topics  that  were  being  discussed. 
Slight  efforts  easily  produced  mental  and  physical  fatigue. 
These  symptoms  were  particularly  striking  in  those  patients 
who  showed  symptoms  pointing  to  involvement  of  the  pit- 
uitary, or  the  basal  ganglia. 

Emotional  instability  was  present  in  many  of  these 
patients.  In  the  majority  it  was  evidenced  in  a  marked 
depression.  They  were  easily  moved  to  tears.  They  worried 
continually;  some  because  they  could  not  sleep,  and  others 
because  their  various  symptoms  persisted  long  after  their 
acute  illness  was  over.  A  number  were  worried  because  they 
still  suffered  from  drowsiness.  A  few  felt  happy  and  uncon- 
cerned; they  displayed  a  feeling  of  well-being  that  was  not  in 
accord  with  what  their  physical  examination  disclosed. 
Two  of  these  patients  were  euphoric  and  presented  a  psycho- 
motor activity  which  was  almost  equal  to  that  seen  in 
hypomanic  states. 

There  were  a  number  of  well-defined  fear  and  compulsion 
neuroses.  One  patient,  a  girl  of  twenty-three,  was  in  constant 
fear  that  she  would  commit  suicide.  She  would  always  have 
to  repress  the  impulse  to  jump  out  of  a  window,  or  throw 
herself  before  a  train.  A  second  patient,  a  man  of  thirty-nine, 
was  in  constant  fear  of  being  arrested,  even  though  he  felt 
positive  that  he  had  done  no  wrong.  A  third  man  was  afraid 
to  stay  home  alone.  He  did  not  know  what  he  feared,  but 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  141 

felt  safe  if  anyone,  even  a  child,  would  stay  in  the  house 
with  him.  He  realized  how  absurd  his  fear  was,  but  main- 
tained that  he  could  not  help  or  understand  it.  A  fourth 
patient,  a  woman  of  thirty-three,  could  not  fall  asleep  because 
she  could  not  keep  her  thoughts  away  from  people  she  knew 
who  had  died.  Another  man  could  not  sleep  because  many 
details  of  the  work  he  had  done  that  day  would  repeatedly 
be  reviewed. 

Disturbance  in  memory,  especially  for  recent  events,  was 
a  common  complaint.  One  patient,  a  student  in  accountancy, 
found  that  since  his  illness,  in  addition  to  defects  in 
memory  for  recent  events,  he  was  having  increasing  diffi- 
culty in  handling  figures. 

Changes  in  disposition  were  very  marked  in  three  children. 
One,  a  boy  of  ten,  had  a  mild  attack  of  encephalitis  in  March, 
1920.  Previous  to  his  illness  his  mother  stated  that  she  had 
great  difficulty  in  managing  this  child,  because  he  was  will- 
ful, quarrelsome,  and  always  up  to  some  mischief.  Since  his 
illness,  he  has  become  docile,  obedient,  and  amiable,  and 
has  stopped  his  quarreling  with  his  brothers  and  sisters. 
His  physical  examination  showed  a  twitching  in  the  muscles 
supplied  by  the  upper  and  lower  branches  of  the  right  facial 
nerve,  and  some  residua  in  the  other  cranial  nerves.  He  had 
gained  20  pounds  in  weight.  His  mental  reactions  were 
slow  and  he  resembled  a  mild  type  of  Froehlich's  syndrome. 
Another  boy  of  thirteen  was  said  previous  to  his  illness  in 
April,  1920,  to  be  an  obedient,  well-mannered,  amiable  child, 
who  never  had  any  difficulties  with  his  companions.  His 
attack  of  encephalitis  was  very  mild,  yet  his  mother  states 
that  since  his  illness,  he  has  become  extremely  irritable, 
quarrelsome,  willful,  and  impossible  to  manage.  He  finds 
great  difficulty  in  his  studies,  and  has  fallen  behind  in  his 
school  work.  He  has  acquired  a  spitting  tic.  Every  few 
seconds  he  has  an  irresistible  desire  to  spit,  and  does  so, 
accompanying  the  act  with  an  explosive  grunt.  He  states  that 
he  cannot  control  this  desire  for  more  than  a  few  minutes  at  a 
time.  The  third  child  began  to  steal  little  things,  and  tell 


i42  ACUTE  EPIDEMIC  ENCEPHALITIS 

many  lies  since  his  illness.  He  had  never  done  these  things 
before.  He  has  become  mentally  slow,  and  cannot  get  along 
in  his  school  work. 

Insomnia  was  a  complaint  in  49  of  the  89  cases.  This  com- 
plaint is  so  striking  that  it  must  be  considered  an  undoubted 
sequel  of  encephalitis.  Almost  all  of  these  patients  stated 
that  it  required  from  one  to  two  hours  before  they  could  fall 
asleep.  Until  the  early  morning  hours  their  sleep  was  easily 
disturbed.  Some  of  the  patients  thought  that  they  could  not 
sleep  well  on  account  of  pains  which  they  suffered.  Others, 
the  majority,  thought  it  was  due  to  the  fact  that  they  could 
not  relax  completely,  and  that  their  minds  were  constantly 
active.  A  similar  insomnia  was  noted  in  many  of  the  patients 
during  the  acute  stage  of  their  illness.  This  symptom,  there- 
fore, should  not  be  considered  a  purely  psychoneurotic  mani- 
festation. Many  of  the  patients  complained  of  excessive 
drowsiness  throughout  the  day;  some  of  them  even  fell  asleep 
during  their  work  hours,  and  were  unable  to  hold  their  posi- 
tions on  this  account.  Yet  when  they  went  to  bed  at  night, 
sleep  was  difficult  and  in  some  cases  even  impossible. 

Based  on  the  publicity  given  the  disease  among  the  laity, 
many  patients  felt  that  they  had  acquired  a  certain  impor- 
tance in  having  passed  through  the  dangers  from  it.  These 
patients  felt  heroic,  yet  they  craved  for  sympathy  and  re- 
assurance. 

Tremors  and  Irregular  Involuntary  Movements.  Fifty-two 
patients  showed  either  tremor  or  some  form  of  irregular 
involuntary  movements.  They  were  present  in  10  out  of  21 
cases  eighteen  months  after  the  acute  stage  of  the  illness 
had  passed;  in  1 1  out  of  21  cases  twelve  months  after;  in  29 
out  of  42  cases  nine  months  after,  and  in  2  out  of  5  cases  six 
months  after  the  acute  illness.  Among  these  52  patients, 
there  were  25  who  showed  a  fine  or  coarse  tremor  of  either 
the  lips,  tongue,  facial  muscles,  arms,  head  or  lower  extremi- 
ties. These  tremors  closely  resembled  those  seen  in  toxic 
states.  The  finer  ones  were  like  those  of  hyperthyroidism, 
and  the  coarser  ones  simulated  those  seen  in  chronic  alco- 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  143 

holism.  These  tremors  were  as  a  rule  not  evident  when  the 
parts  were  at  rest,  but  became  apparent  when  the  parts  were 
put  into  action.  Ten  of  the  52  patients  showed  a  tremor  that 
was  spontaneous,  present  while  the  parts  were  at  rest,  and  as 
a  rule  limited  to  the  distal  parts  of  the  extremity  affected. 
Emotional  stress  caused  an  exaggeration  of  the  tremor,  and 
it  was  said  to  disappear  during  sleep.  This  tremor  was  like 
those  seen  in  paralysis  agitans.  In  3  of  the  cases  it  was  pres- 
ent in  both  hands;  in  3  others  it  was  present  only  in  one 
hand;  in  3  cases  the  arm  and  leg  were  the  seat  of  the  tremor, 
and  in  1  case  both  arms  and  legs  were  involved. 

Ataxic  tremors  of  the  intentional  type  were  noted  in  5 
cases.  In  3  of  these  patients  the  tremor  was  present  in  both 
arms;  in  1  case  the  head  and  both  arms  were  affected,  and  in 
the  other  case  it  was  present  in  all  of  the  extremities.  These 
tremors  were  present  only  when  the  parts  affected  were  in 
action.  They  were  characterized  by  large,  coarse,  irregular 
oscillations,  with  a  variable  range  of  movement  which  tended 
to  increase  as  the  goal  was  reached.  They  closely  resembled 
the  tremors  seen  in  multiple  sclerosis  and  cerebellar  disease. 
One  of  the  patients  in  addition  to  the  tremor  had  nystagmus, 
scanning  speech,  and  ataxia  in  her  gait.  She  was  however 
progressively  getting  better. 

Five  patients  had  a  rapid  clonic  twitch  of  the  muscles 
supplied  by  one  or  more  branches  of  the  facial  nerve.  This 
twitching  closely  resembled  the  muscular  response  obtained 
when  the  nerve  is  stimulated  with  an  electrical  current.  It 
occurred  every  few  seconds,  was  very  rapid,  and  always  defin- 
itely limited  anatomically  to  the  muscles  supplied  by  the 
particular  branch  involved. 

Three  of  the  patients  showed  choreiform  movements  of  the 
tongue,  face  or  extremities.  Three  others  had  fibrillary  tre- 
mors of  the  tongue;  2  associated  with  unilateral  atrophy  of 
the  tongue.  One  patient  showed  myoclonic  movements  of  the 
perineal  muscles  one  year  after  the  acute  illness. 

Disturbance  in  Attitude  and  Gait.  There  were  14  of  the 
89  cases  who  showed  disturbance  in  their  attitude  and  gait. 


144  ACUTE  EPIDEMIC  ENCEPHALITIS 

Four  patients  showed  the  typical  attitude  and  gait  of  paraly- 
sis agitans.  All  4  were  children ;  the  youngest  was  seven  and  a 
half  and  the  oldest  was  sixteen  years.  Five  other  patients 
showed  similar  attitudes,  but  in  addition  walked  with  a 
hemiplegic  gait.  Loss  of  associated  movements  was  present 
in  5  of  these  9  cases.  Propulsion  was  present  in  4  and  in  one 
of  these  retropulsion  was  also  present.  Three  patients  walked 
with  a  spastic  paraplegic  gait,  and  2  patients  walked  with  a 
right  hemiplegic  gait. 

Disturbance  in  Tonus  and  Reflexes.  Tonus  was  disturbed 
in  17  cases.  In  4  of  these  there  was  slight  increase  in  the  mus- 
cle tone.  In  5  there  was  a  moderate  increase,  but  not  suffi- 
cient to  produce  the  "cog-wheel  phenomenon. "  In  5  others 
there  was  a  marked  increase  in  tonus  and  the  cog-wheel 
phenomenon  was  elicited.  Two  patients  had  diminished  tonus 
in  the  muscles  of  the  lower  extremities,  and  one  patient  had 
dystonia  in  the  muscles  in  both  thighs. 

The  deep  reflexes  were  altered  in  27  cases.  In  11  of  these 
patients,  the  deep  reflexes  were  greatly  increased,  but  equally 
so  on  both  sides.  In  15  the  deep  reflexes  were  unequal,  being 
more  active  on  one  side  than  the  other.  In  one  patient  the 
right  ankle-jerk  was  absent  and  the  left  diminished,  while  the 
knee-jerks  were  both  equally  hyperactive. 

The  Babinski  reflex  was  definitely  present  in  6  cases  and 
doubtful  in  one.  In  2  of  the  6  patients  it  was  present  on  both 
sides,  while  in  the  other  4  it  was  present  only  on  one  side. 
Three  of  these  patients  presented  clinically  paralysis  agitans 
features.  In  one  of  the  patients  there  was  associated  with  a 
bilateral  Babinski,  hypotonus  at  the  ankles,  and  loss  of  the 
right  ankle- jerk. 

Cranial  Nerve  and  Pupillary  Disturbances.  There  was 
some  disturbance  in  the  cranial  nerves  present  in  57  of  the 
89  cases.  In  36  of  these,  slight  facial  inequality  was  present 
on  one  side;  2  others  showed  bilateral  facial  weakness.  This 
slight  disturbance  in  facial  innervation  in  the  majority  of  the 
cases  seemed  to  be  supranuclear  in  origin.  Nine  of  the 
patients  showed  both  the  facial  and  external  rectus  involve- 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  145 

ment;  2  showed  involvement  of  the  external  rectus  alone; 
2  showed  atrophy  of  the  tongue,  and  1  patient  had  fibrillary 
tremor  without  the  atrophy  of  the  tongue.  One  patient 
showed  deviation  of  the  tongue  to  the  right,  and  one  patient 
had  paralysis  of  the  soft  palate  on  the  right  side.  Five  of  our 
patients  showed  some  disturbance  in  the  optic  nerves  during 
the  acute  stage  of  their  illness.  In  this  reexamination  only 
one  patient  was  found  to  have  definite  changes.  This  girl 
had  a  temporal  pallor  of  the  right  nerve  and  almost  complete 
atrophy  of  the  left  nerve  head.  No  optic  neuritis  was  noted 
during  the  acute  stage  of  this  patient's  illness.  She  also  com- 
plained of  diminution  of  her  hearing  on  the  left  side,  but 
there  were  no  objective  signs  of  disturbed  function  present. 

Incomplete  ptosis  was  present  on  one  side  in  16  patients; 
it  was  present  on  both  sides  in  7  others.  The  pupils  were 
unequal  in  26  of  the  89  cases.  Irregularity  of  the  outline  of 
the  pupils  was  noted  in  5  patients.  Disturbance  in  the  reflex 
to  light  or  convergence  was  present  in  26  cases.  In  10  of  these 
26  patients  there  was  a  sluggish  and  incomplete  reaction 
to  light  in  both  pupils;  in  7  others  only  one  pupil  was  affected. 
In  4  patients  there  was  a  sluggish  reaction  to  light  on  one  side 
and  complete  loss  of  reaction  on  the  other  side,  with  sluggish 
reactions  to  convergence  in  one  or  both  of  the  pupils.  Argyll- 
Robertson  pupils  were  present  in  5  cases.  In  3  of  these 
patients  it  was  present  on  one  side  only,  and  in  2  it  was  pre- 
sent on  both  sides.  One  patient,  the  girl  who  showed  the 
atrophy  in  the  nerves,  had  what  appeared  to  be  on  rough 
testing,  a  left  homonymous  hemianopsia;  the  pupils  in  her 
case  were  sluggish,  but  Wernicke's  reaction  was  not  tested. 

Epilepsy.  Three  patients  suffered  from  grand  mal  or 
petit  mal  attacks  since  recovering  from  their  acute  illness. 
The  patient  with  the  grand  mal  attacks  had  had  since  his 
acute  illness  in  January,  1920,  4  seizures  in  which  there  was 
complete  loss  of  consciousness  for  a  period  of  from  five  to 
ten  minutes.  He  also  had  a  great  many  seizures  in  which  he 
did  not  lose  consciousness.  The  other  2  patients,  both  males, 
one  twenty-seven  and  the  other  forty-eight  years  of  age, 
10 


146  ACUTE  EPIDEMIC  ENCEPHALITIS 

have  been  suffering  since  their  acute  illness,  from  attacks  of 
spasmodic  contraction  of  the  right  side  of  the  face.  These 
attacks  come  on  at  irregular  intervals,  last  from  thirty  to 
sixty  seconds,  and  in  the  older  of  the  two  patients  are  accom- 
panied by  vertigo,  confusion,  and  difficulty  in  speech  which 
lasts  from  one  to  two  minutes.  If  standing  when  the  seizure 
occurs,  they  must  grasp  some  nearby  object  to  keep  from 
falling.  Any  number  of  attacks  occurred  each  day. 

Other  Residual  Signs  and  Symptoms.  Headache  and  gen- 
eralized pains  in  various  parts  of  the  body  were  a  most  com- 
mon complaint.  The  headaches  presented  no  special  char- 
acteristics; they  were  located  over  any  part  of  the  cranium, 
and  usually  diffuse.  Burning  on  the  top  of  the  head  and 
behind  the  eyes  was  also  a  common  complaint.  The  pains  in 
the  body  and  extremities  were  present  in  the  patients  who 
had  suffered  from  the  neuritic  form  of  encephalitis.  Some  of 
these  patients  state  that  their  pains  were  as  severe  at  the 
present  time  as  they  had  been  during  the  acute  stage  of  their 
illness.  Most  of  them  however  claimed  the  pains  were  less 
severe. 

Exophthalmos  was  noted  in  4  cases.  It  was  present  on 
both  sides,  and  was  unaccompanied  by  any  other  signs  of 
hyperthyroidism  with  the  exception  of  tremor  of  the  hands. 
Tremor  of  the  hands  however  was  present  in  so  many  of  the 
patients  that  it  could  not  definitely  be  attributed  to  hyper- 
thyroid  activity  in  these  patients. 

Increase  in  weight  was  noted  in  15  cases.  In  13  of  these 
the  amount  gained  above  the  best  previous  weight  was  15,  15, 
17,  20,  20,  25,  25,  35,  38,  45,  48,  50,  and  95  pounds.  In  2 
the  amount  gained  was  not  definitely  known.  Many  of  these 
patients  showed  some  other  manifestations  of  disturbed 
pituitary  function. 

Progressive  Cases.  Seven  of  the  patients  showed  definite 
evidence  of  progression  in  their  disease  at  the  time  they  were 
examined.  Five  of  these  were  of  the  paralysis  agitans  type. 
They  showed  the  typical  attitude,  gait,  tremor,  rigidity,  and 
restlessness  seen  in  this  disease.  In  some  of  these,  disturbance 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  147 

of  associated  movements  was  also  present.  One  of  the  other 
2  patients,  a  male,  thirty  years  of  age,  has  gained  since  his 
illness  sixteen  months  ago,  95  pounds  in  weight;  he  is  always 
drowsy  and  mentally  sluggish.  Six  months  ago  fibrillary 
tremors  and  atrophy  of  the  left  half  of  his  tongue  were 
noted.  He  is  progressively  getting  worse.  The  other  patient 
was  taken  ill  in  November,  19 19.  At  that  time  her  physical 
condition  showed  bilateral  facial  weakness,  tremor  of  the 
tongue,  intention  tremor  and  rigidity  with  cogwheel  pheno- 
mena in  both  arms,  and  the  attitude  and  gait  of  paralysis 
agitans.  In  December,  1920,  reexamination  showed  she 
walked  with  a  peculiar  gait,  not  unlike  that  seen  in  a  case  of 
progressive  torsion  spasm;  there  were  choreiform  and  choreo- 
athetoid  movements  of  the  face,  neck,  shoulders,  and  lower 
extremities.  There  was  constant  uncontrollable  grinding  of 
her  teeth.  While  seated,  her  pelvis  and  lower  extremities  were 
constantly  being  twisted  by  involuntary  spasms  of  the 
muscles.  Her  pupils  were  irregular  and  almost  completely 
immobile  in  their  reactions  to  light  and  convergence.  There 
was  slight  flatening  of  the  facial  folds  on  the  right  side. 
Dystonia  was  present  in  the  muscles  of  the  lower  extremities. 
The  deep  reflexes  were  present  and  equally  active  on  both 
sides;  Babinski  was  not  elicited. 

The  majority  of  the  other  patients  admitted  that  they 
were  gradually  getting  better.  Even  though  they  had  many 
complaints,  they  stated  that  these  symptoms  were  far  less 
severe  than  they  were  at  the  time  when  they  left  the  hospital. 

Mortality.  Among  the  145  patients  admitted  to  the 
hospital  29  died.  This  gives  a  mortality  rate  of  20  per  cent 
among  these  patients.  Notice  of  the  death  of  one  other 
patient  after  she  left  the  hospital  was  received. 

Prognostic  Conclusions.  Sufficient  time  has  not  yet 
elapsed  since  the  acute  illness,  neither  is  the  number  of  cases 
in  this  study  large  enough  to  warrant  drawing  absolute 
conclusions  as  to  what  the  ultimate  prognosis  will  be  in  these 
patients.  There  are,  however,  a  number  of  striking  facts 
that  might  be  emphasized. 


148  ACUTE  EPIDEMIC  ENCEPHALITIS 

i.  Psychic  functions  in  some  form  or  another  were  dis- 
turbed in  55  per  cent  of  these  patients. 

2.  Insomnia  was  present  in  55  per  cent  of  the  cases. 

3.  Tremor  and  irregular  involuntary  movements  were 
present  in  58  per  cent  of  the  cases. 

4.  The  deep  reflexes  were  altered  in  30  per  cent,  and 
muscle  tonus  was  disturbed  in  18  per  cent  of  the  cases. 

5.  The  cranial  nerves  showed  residual  signs  in  64  per  cent 
of  the  cases. 

6.  Pupillary  disturbances  were  found  in  30  per  cent  of  the 
cases;  5  patients  showed  Argyll-Robertson  pupils. 

7.  About  8  per  cent  of  the  cases  showed  signs  of  progres- 
sion at  the  time  they  were  examined. 

8.  The  mortality  among  the  145  patients  admitted  to  the 
Mt.  Sinai  Hospital  was  20  per  cent. 

From  the  above  findings  one  might  venture  the  following 
tentative  prognosis.  Probably  less  than  20  per  cent  of  the 
patients  who  become  ill  with  epidemic  encephalitis  die 
during  the  acute  stage,  as  usually  only  the  more  severe 
cases  reach  the  hospital.  Of  those  who  survive  the  acute 
stage  of  the  illness,  about  10  per  cent  may  develop  a  progres- 
sive disease  of  the  central  nervous  system.  The  remainder 
will  make  a  good  functional  recovery  in  from  six  to  twenty- 
four  months,  with  the  probability  of  progressive  approach 
to  the  normal  after  that  period. 

The  following  questions  submitted  to  Dr.  Grossman  be- 
fore the  commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Tilney:  Would  you  mind  stating  the  percentage  of  total 
recoveries,  that  is  without  any  sequelae. 

Dr.  Grossman:  That  is  rather  difficult  because  I  did  not  take 
that  up.  Most  of  the  patients  showed  something  and  it  was  very 
difficult  to  state  how  many.  I  did  not  take  that  point  up  specially. 

Dr.  Tilney:  There  were  no  complete  recoveries  as  far  as  you 
are  able  to  say? 

Dr.  Grossman:  Very  few. 


DIAGNOSIS,  COURSE  AND  PROGNOSIS         149 

Dr.  Sachs:  May  I  ask  Dr.  Grossman  to  make  a  statement. 
You  say  that  actual  psychoses  had  not  been  observed  or  they  were 
not  included? 

Dr.  Grossman:  They  were  not  included  in  this  study. 

Dr.  Sachs  :  Did  you  observe  any? 

Dr.  Grossman:  One  case  which  I  did  not  include  in  this  study. 

Dr.  Sachs:  Only  one  psychosis  which  you  could  attribute  to 
this  disease? 

Dr.  Grossman:  Yes. 

Dr.  Barker:  I  would  like  to  ask  if  the  patients  showing  neuras- 
thenic or  psychasthenic  states  after  encephalitis  were  neurasthenic 
or  psychasthenic  before?  In  other  words,  did  these  neurasthenias 
and  psychasthenias  come  as  entirely  new  things  in  the  life  of  the 
patient? 

Dr.  Grossman:  I  went  into  that  question  very  carefully,  and 
in  most  of  these  patients  it  was  stated  that  they  were  different 
after  the  disease  than  they  had  been  before.  Of  course,  the  actual 
condition  of  the  patients  I  am  not  in  a  position  to  state.  It  is 
merely  the  statement  of  the  relatives  or  the  patients  themselves 
that  I  have  to  go  by. 

Dr.  Barker:  Another  question  I  would  like  to  ask  is  whether 
or  not  there  is  going  to  be  any  way  of  distinguishing  between 
these  patients  with  residual  Argyll-Robertson  pupils  and  patients 
who  have  Argyll-Robertson  pupils  due  to  a  burnt  out  tabes? 

Dr.  Grossman  :  There  is  only  one  way,  that  is  to  take  the  general 
picture  into  consideration.  One  or  two  of  these  patients  had  no 
other  evidence  except  the  Argyll-Robertson  pupil — no  other 
evidence  of  the  disease  anywhere.  Without  the  Wassermann  test 
it  would  be  difficult. 

Dr.  Sachs:  May  I  ask  one  more  question?  Did  you  make  this 
statement  that  the  residual  headaches  were  generally  occipital? 

Dr.  Grossman:  No.  My  statement  was  that  they  occurred  in 
any  part  of  the  head;  there  was  no  distinctive  localization. 
Some  complained  of  one  part  and  some  of  another — different  parts 
of  the  head.  There  was  no  grouping  that  one  could  make. 

Dr.  Taylor:  Was  the  atrophy  of  the  tongue  unilateral  or 
bilateral? 

Dr.  Grossman:  Unilateral. 

Dr.  Taylor:  In  a  general  way,  what  was  the  age  of  the  patients 
who  had  increased  in  weight? 


150  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Grossman:  The  ages  vary.  Many  of  them  were  children. 
One  man,  I  believe,  was  thirty  years  of  age,  but  the  majority 
of  the  patients  were  in  the  younger  groups.  These  were  abnormal 
increases,  such  that  the  parents  of  the  children  themselves  noted 
it.  They  wanted  to  know  why  it  was  that  these  children  had 
increased  so  rapidly.  It  was  a  rapid  increase  in  weight  noticeable 
to  the  parents  of  the  children,  disproportionate  to  their  growth. 

Dr.  Dana:  I  do  not  know  whether  it  is  not  true  that  in  children 
who  have  acute  infections  and  get  over  them  there  is  not  some- 
times a  rapid  increase  in  growth — in  any  kind  of  infection. 

Dr.  Grossman  :  That  may  be  true  but  this  increase  occurred  in 
only  a  limited  percentage  of  these  children,  so  much  so  that  it  was 
evident  to  the  parents,  and  was  a  point  that  they  themselves 
volunteered.  I  did  not  ask  for  it.  They  said  these  children  were 
growing  abnormally  stout  in  a  short  time.  It  was  a  growth  of  fat, 
as  a  rule.  This  covers  a  study  of  six  months  to  two  years.  That 
varies;  in  different  individuals  the  study  extends  over  two  years. 

Dr.  Sachs:  But  the  increase  in  weight  was  chiefly,  as  I  under- 
stood it,  after  the  illness? 

Dr.  Grossman:  Shortly  after  the  illness.  It  was  usually  asso- 
ciated with  mental  sluggishness.  These  children,  as  a  rule,  became 
backward  in  their  studies;  they  didn't  seem  to  be  interested,  and 
they  were  inclined  to  be  drowsy  and  disinclined  to  any  physical 
activities. 

Dr.  Dana:  Would  you  consider  this  increase  in  weight  a  pitui- 
tary symptom? 

Dr.  Grossman  :  It  struck  me  as  if  it  might  be  on  account  of  this 
sluggishness  and  general  lack  of  interest  in  any  type  of  work. 
In  one  patient  there  was  no  doubt  in  my  mind  that  it  was  a  pitui- 
tary condition;  there  were  headaches  with  it  and  various  other 
phenomena. 

Dr.  Timme:  Have  you  noticed  in  any  cases  a  general  muscular 
atrophy? 

Dr.  Grossman:  I  have  not  noticed  it  in  any  of  these  cases. 

Further  Observations  in  Prognosis  (Junius  W. 
Stephenson).  These  conclusions  were  based  on  a  study  of 
95  cases  observed  at  the  Neurological  Institute  and  Bellevue 
Hospital,  New  York  City.  Sixty  of  the  cases  had  been 
recently  examined  by  the  author,  and  of  the  remaining  35, 
a  majority  reported  their  condition  through  correspondence. 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  151 

No  case  was  considered  in  which  the  illness  had  not  extended 
over  a  period  of  six  months,  the  large  majority  being  nine  to 
twelve  months.  According  to  the  predominant  symptoms, 
the  cases  were  classified  as  follows:  Parkinsonian  type, 
33  per  cent;  spinal  type,  20  per  cent;  cranial  nerve  and 
diplopia  type,  20  per  cent;  cerebral  type,  10  per  cent; 
mixed  type,  17  per  cent. 

Parkinsonian  Type.  All  the  cases  examined  showed 
improvement,  but  no  case  showed  a  complete  recovery. 
One  case  reported  no  improvement.  Fully  75  per  cent 
complained  of  various  functional  symptoms,  such  as  head 
and  spine  pains,  fatigability,  lack  of  concentration  and 
other  neurasthenic  symptoms.  No  actual  obsessions  were 
encountered.  The  functional  symptoms  almost  invariably 
appeared  between  the  third  and  fifth  month  after  the  onset 
of  the  illness.  One  case  developed  a  psychosis.  This  patient 
suicided  nine  months  after  the  onset  of  illness.  One  boy, 
eight  years  of  age,  five  months  after  the  onset  of  illness, 
showed  evidence  of  moral  derangement.  This  boy,  prior  to 
the  illness,  had  been  a  model  child,  but  now  was  given  to 
thieving,  lying  and  even  attempted  arson.  He  showed  one 
testicle  considerably  smaller  than  the  other,  but  the  mother 
could  not  state  whether  or  not  that  existed  prior  to  the 
illness.  It  was  observed  that  in  those  cases  in  which  there 
were  gross  tremors  associated  with  lethargy,  when  improve- 
ment did  begin,  it  progressed  more  rapidly  than  those  which 
showed  fine  tremors.  There  was  one  distinct  relapse.  This 
patient,  a  woman  thirty-five  years  of  age,  five  months  after 
the  onset  of  the  illness,  was  in  condition  so  that  she  could 
perform  her  household  duties  in  a  normal  manner.  Later,  she 
gradually  became  "dopey"  during  the  day,  and  wakeful  at 
night.  In  addition,  her  tremor  became  more  aggravated,  and 
whereas  her  mask-like  expression  had  almost  disappeared, 
upon  examination  she  showed  a  distinct  masked  facies. 
Objectively  all  the  cases  showed  rhythmic  tremors  of  varying 
degrees,  with  hyperactive  reflexes.  There  appeared  a  tendency 
for  the  mask-like  expressions  to  clear  up. 


i52  ACUTE  EPIDEMIC  ENCEPHALITIS 

Spinal  Type.  With  the  exception  of  two,  all  showed  a 
slowly  progressive  improvement,  but  none  was  free  of 
symptoms.  The  disappearance  of  symptoms  was  in  the 
following  sequence:  myoclonia,  tremor,  pain.  In  practically 
all  the  cases,  sticking  pains  were  at  times  distressing.  It  was 
observed  that  in  those  cases  beginning  acutely  with  moderate 
temperature  and  severe  pains,  improvement,  when  it  began, 
was  more  rapid  than  in  those  in  which  onset  was  subacute. 
There  were  two  distinct  relapses,  and  in  both  cases,  the 
relapse  occurred  about  five  months  after  the  onset  of  the 
illness.  One,  a  man  thirty  years  of  age,  had  a  recurrence  of 
pronounced  intensity;  severe  pains,  gross  myoclonus  and  tre- 
mors. His  deep  reflexes  were  hyperactive,  but  he  showed  no 
distinct  pyramidal  disturbance.  The  original  onset  of  this  case 
was  very  slow;  the  relapse  quite  acute.  The  other,  a  girl 
seventeen  years  of  age,  in  addition  to  the  clinical  picture  of 
the  original  onset,  now  showed  typical  trophic  sores,  and 
whereas  previously  her  deep  reflexes  were  overactive,  they 
were  now  very  sluggish.  There  was  some  impairment  of  her 
joint  sense  inasmuch  as  at  times  she  was  very  much  confused 
in  recognizing  the  position  of  her  toes.  Vibratory  sense  was 
intact.  In  both  cases  "sticking  pains"  were  extremely  dis- 
tressing. Up  to  the  time  of  the  relapse  both  cases  showed 
slow  but  steady  improvement.  Sequelae  of  functional  type 
were  also  observed  in  these  cases,  but  less  frequently  than 
in  the  Parkinsonian  type. 

Cranial  Nerve  with  Diplopia  Type.  This  type  represents 
that  class  in  which  objective  findings  revealed  multiple 
cranial  nerve  involvement  with  diplopia.  The  onset  in  the 
majority  was  more  or  less  acute.  The  diplopia  persisted  from 
a  few  days  to  six  weeks.  Of  the  cranial  nerves  the  sixth 
was  the  first  to  clear  up.  The  most  persistent  objective  finding 
was  a  thalamic  facies.  In  the  majority  of  cases  that  had 
shown  slowness  of  light  reaction,  there  was  a  gradual  return 
to  normal.  No  relapse  was  observed.  No  functional  sequelae 
were  observed.  Improvement  in  this  class  was  more  rapid 
than  in  any  other  of  the  types  quoted,  and  apparently  this 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  153 

particular  type  will  ultimately  prove  the  most  favorable  so 
far  as  complete  recovery  is  concerned. 

Cerebral  Type.  This  type  included  those  cases  showing 
hemiplegias,  aphasias  and  other  distinctly  cerebral  mani- 
festations. None  had  completely  recovered,  but  in  all  there 
had  been  a  gradual  but  very  slow  recovery,  both  subjectively 
and  objectively.  Two  cases  which  had  previously  shown  a 
papilledema  were  now  free  of  it.  Where  the  onset  was  acute 
and  the  illness  profound,  if  the  individual  survived  the 
acute  symptoms,  recovery  was  more  rapid  than  in  the  less 
acute  cases. 

Mixed  Type.  This  included  any  combination  of  the 
above  types,  and  pursued  a  course  concomitant  with  the  type 
predominating. 

Mortality.  Of  a  series  of  57  cases  in  Bellevue  Hospital 
there  were  ten  deaths,  giving  a  mortality  of  approximately 
20  per  cent.  Of  the  ten  deaths,  four  were  adults  and  six  were 
children  below  the  age  of  ten.  Of  38  cases  recorded  at  the 
New  York  Neurological  Institute,  there  were  four  deaths: 
three  adults,  one  child.  In  those  children  in  whom  death 
occurred,  the  onset  was  acute,  with  high  temperature  and 
delirium,  and  the  average  duration  of  the  illness  was  seven 
to  eight  days.  In  the  adults,  the  symptoms  were  not  so  acute, 
nor  was  there  such  a  pronounced  rise  of  temperature,  and 
the  duration  of  the  illness  was  from  ten  days  to  six  weeks. 
It  was  observed  that  adults  showed  a  rather  constant  mor- 
tality of  approximately  10  per  cent,  whereas  children 
approximated  15  per  cent. 

This  disease  presents  so  many  different  clinical  pictures 
(the  three  epidemics  being  entirely  different  from  one  another) 
that  at  this  time  no  one  can  formulate  any  definite  prognostic 
data.  However,  the  disease  does  show  a  distinct  tendency  to 
a  spontaneous  improvement,  but  in  my  opinion  a  period  of 
from  two  to  three  years  was  necessary  to  determine  just  to 
what  degree  improvement  would  progress;  though  relapses 
do  occur,  they  are  infrequent.  I  am  apprehensive  that  the 
Parkinsonian  and  spinal  types  would  undoubtedly  augment 


154  ACUTE  EPIDEMIC  ENCEPHALITIS 

our  existing  army  of  neurasthenics.  It  is  my  opinion  that 
psychotic  sequelae  would  be  infrequent.  The  more  acute  the 
onset,  the  more  rapid  would  be  the  improvement.  The  grosser 
the  tremor  in  the  Parkinsonian  and  spinal  types,  the  more 
rapid  the  improvement.  Papilledema  occurring  during  the 
disease  shows  a  tendency  to  spontaneous  subsidence.  The 
cranial  nerve  and  diplopia  type  offers  the  most  favorable 
outlook.  The  mortality  can  be  fairly  accurately  estimated  for 
adults  as  10  per  cent;  for  children  under  the  age  of  ten,  ap- 
proximately 15  per  cent. 

The  following  questions  submitted  to  Dr.  Zabriskie  before 
the  Commission,  together  with  the  answers  to  them,  are  here 
reported  verbatim. 

Dr.  Sachs:  I  would  like  to  ask  whether  Dr.  Zabriskie  thinks 
from  his  own  experience  or  the  experience  of  others  that  frequent 
lumbar  punctures  have  really  been  of  some  benefit? 

Dr.  Zabriskie  :  It  has  not  been  my  experience,  and  as  far  as  I 
can  find  in  the  literature  the  opinions  vary  greatly,  but  the  pre- 
ponderance of  opinion  is  that  they  have  no  specific  effect. 

Dr.  Sachs:  It  has  not  even  hastened  the  period  of  recovery? 

Dr.  Zabriskie:  Some  have  reported  that  it  has  but  ior  the 
most  part  I  think  not. 

Dr.  Taylor:  May  I  ask  how  your  atropine  has  been  admin- 
istered? 

Dr.  Zabriskie:  Both  by  mouth  and  intravenously. 

Dr.  Taylor:  And  what  has  been  the  result — either  yours  or  the 
experience  of  others? 

Dr.  Zabriskie:  My  own  experience  has  been  entirely  by 
mouth.  The  only  note  I  have  been  able  to  find  on  that  has  been 
among  the  French  in  which  they  recommend  the  mouth  method 
as  preferable  to  the  intravenous  because  of  the  more  rapid  elimi- 
nation by  the  intravenous  method. 

Dr.  Taylor:  How  about  the  arsenical  preparation? 

Dr.  Zabriskie:  There  have  only  been  a  few  cases  reported  of 
that,  and  one  man  reports  beneficial  effects.  I  have  forgotten  his 
name.  Netter  disapproves  of  it  because  he  found  bad  results 
in  2  cases,  I  think. 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  155 

Dr.  Taylor:  Do  you  feel  that  any  of  these  things  have  done  any 
good  really? 

Dr.  Zabriskie:  None  of  them.  One  recommendation  I  have  found 
is  the  rather  cruel  method  of  fixation  abscess.  Netter  reports  79 
cases;  in  52  the  abscess  was  used,  and  in  27  the  abscess  was  not 
used.  His  results  were  ten  deaths  with  the  abscess  and  thirteen 
deaths  in  the  cases  without  abscess.  Of  those  ten  deaths  with  the 
use  of  the  turpentine  injection,  six  did  not  go  to  abscess  formation, 
and  therefore  he  discards  them.  Of  the  remaining  four,  two  died 
before  the  abscess  had  had  time  to  develop,  and  that  only  left 
two  deaths  in  which  the  abscess  had  formed,  and  both  those 
deaths  were  in  pregnant  women. 

Dr.  Sachs:  Have  there  been  any  distinct  reports  regarding  the 
use  of  the  serum  from  convalescent  patients? 

Dr.  Zabriskie:  That  has  been  tried  and  on  the  whole  unfavor- 
ably reported  upon.  I  mean  to  say  reported  unfavorably  in  the 
sense  that  it  apparently  had  no  influence  on  the  patient.  They 
were  all  injected  intraspinally. 

CONCLUSIONS    OF   THE    COMMISSION 

i.  Diagnosis.  Up  to  the  present  time  through  lack  of 
definite  criteria  separating  epidemic  encephalitis  as  an 
entity  from  all  other  disturbances,  a  great  many  cases  of  the 
disease  may  possibly  be  of  such  mild  character,  or  may  occur 
in  moderately  immune  individuals,  that  the  development 
of  the  affection  may  never  reach  the  degree  of  maturity 
expressed  by  neuropathic  or  psychopathic  states,  and  hence 
in  the  classification  advanced  in  this  chapter  such  possible 
cases  find  no  group  to  which  they  may  become  attached. 
There  is,  therefore,  still  to  be  sought  the  basic  criterion.  For 
those  cases  that  have  clinically  been  recognized  as  epidemic 
encephalitis,  the  foregoing  classification  seems  to  the  Com- 
mission to  be  sufficiently  definitive  and  adequate  in  scope. 

2.  Differential  Diagnosis.  A  similar  statement  may  be 
made  here  as  to  our  inability  to  separate  mild  and  abortive 
cases  of  epidemic  encephalitis  from  other  conditions  which 
they  simulate.  Thus,  influenza  may  have  various  neuritides  as 
accompaniments  or  sequelae,  as  well  as  psychopathic  states. 


156  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  spinal  fluid  pleocytosis  is  not  a  necessary  factor  in 
epidemic  encephalitis  and  hence  cannot  be  accepted  as  a 
strictly  differential  point.  Even  more  difficult,  if  not  impossi- 
ble, would  be  the  diagnosis  between  epidemic  encephalitis 
and  certain  forms  of  anterior  poliomyelitis.  This  difficulty 
is  well  brought  out  by  the  special  paper  on  the  subject. 

The  Commission  would  therefore  submit  that  only  in  the 
moderately  well-marked  cases  of  either  disease  is  the  diagno- 
sis fairly  easily  made,  but  that  in  formes  frustes,  or  in  mild 
types,  the  diagnosis  at  the  present  state  of  our  knowledge 
might  well  be  impossible. 

3.  Prognosis.  The  opinion  of  the  Commission  upon  this 
phase  of  the  research  problem  is  that  for  the  number  of 
cases  examined  by  two  independent  observers,  the  results 
are  sufficiently  uniform  to  be  tentatively  accepted  until  such 
time  as  a  much  greater  number  of  patients  shall  have  under- 
gone examination.  One  fact,  however,  must  be  borne  in 
mind.  All  the  cases  examined  were  severe  hospital  cases  and 
hence  the  Commission  feels  that  the  mortality  rate  as  given, 
as  well  as  the  other  rates,  should  properly  be  limited  in 
their  application  to  "severe  hospital  cases."  The  total 
number  here  reported  is  only  about  170.  Furthermore,  a 
longer  time  must  have  elapsed  from  the  onset  of  the  disease 
to  the  examination  period.  In  the  meanwhile,  however,  the 
conclusions  given  seriatim  by  Dr.  Grossman  at  the  end  of 
his  paper  seem  well  grounded.  The  mortality  of  the  disease  is 
given  as  from  10  to  20  per  cent  by  both  observers  for  the 
acute  stage  of  the  disease.  The  Commission  regrets  the 
absence  of  figures  giving  the  number  of  cases  that  presented 
no  sequelae  whatever;  in  other  words,  complete  recoveries. 
The  consensus  of  opinion,  however,  is  that  these  are  very 
few.  About  8  per  cent  of  the  cases  examined  showed  signs 
of  progression  of  the  symptoms.  It  must  be  remembered,  in 
going  over  these  papers,  that  the  cases  represented  are 
practically  all  severe  ones  with  marked  symptoms  of  involve- 
ment of  the  central  nervous  system.  Many  of  the  milder 
forms,  the  Commission  believes,  never  reached  the  hospitals, 


DIAGNOSIS,  COURSE  AND  PROGNOSIS  157 

and  many  of  these  in  all  probability  had  no  sequelae  of 
importance. 

The  cases  of  recrudescence  of  the  symptoms  in  the 
course  of  the  disease  are  discussed  in  the  chapter  on 
symptomatology. 

4.  Treatment.  Not  knowing  the  causative  factors 
involved  in  the  pathogenesis  of  epidemic  encephalitis,  it 
becomes  impossible  at  present  to  outline  a  rational  therapy. 
And  so,  from  no  treatment,  through  the  entire  gamut  of 
remedial  agents  to  the  medieval  "fixation  abscess," 
everything  seems  to  have  been  essayed.  There  are  no  statis- 
tical tables  available  for  comparison  as  yet  and  no  individual 
treatment  has  been  extolled  even  by  its  orginator  to  a  degree 
which  warrants  closer  examination  of  the  returns.  For  this 
reason,  the  Commission  feels  itself  constrained  to  make  no 
report  upon  the  merits  of  any  particular  method  of  com- 
bating the  disease.  There  likewise  seems  no  basis  for  a 
rational  preventive  therapy  other  than  a  non-specific  one 
applicable  to  all  diseases  of  infectious  character. 


Chapter  VI 

MORBID  ANATOMY:  PATHOLOGY  OF  THE  BRAIN 

AND  SPINAL  CORD;  LESIONS  OUTSIDE 

THE  NERVOUS  SYSTEM 

IN  the  chapter  on  the  pathology  of  epidemic  encephalitis 
the  commission  submits  its  opinion  concerning  the  gross 
and  microscopic  alterations  caused  by  this  disease.  This 
opinion  is  based  upon  the  reported  investigations  of  Dr. 
James  B.  Ayer  of  Boston,  covering  the  gross  and  micro- 
scopic lesions  in  the  nervous  system;  of  Dr.  William  G. 
Spiller  of  Philadelphia,  dealing  with  the  detailed  pathological 
changes  in  five  brains  and  two  spinal  cords;  of  Dr.  Hubert  S. 
Howe  of  New  York,  describing  the  microscopic  appearance  of 
the  several  endocrine  organs;  of  Dr.  William  Boyd  of  Mani- 
toba, Canada,  revealing  the  pathological  alterations  in  parts 
of  the  body  other  than  the  nervous  system;  and  of  Dr. 
George  B.  Hassin  of  Chicago,  contrasting  the  histological 
changes  in  the  nervous  system  due  to  epidemic  encephalitis 
with  those  due  to  lead  and  other  poisons. 

This  section  of  the  report  also  includes  the  questions 
submitted  by  the  Commissioners  to  the  investigators  men- 
tioned above,  together  with  the  answers  made  during  the 
public  hearings  of  the  Commission.  In  many  instances 
the  answers  to  the  questions  proposed  by  the  members  of 
the  Commission  shed  much  light  upon  points  in  the  investi- 
gation which  might  otherwise  remain  obscure  or  in  doubt.  For 
this  reason  it  has  been  deemed  advisable  to  reproduce  the 
verbatim  report  of  the  questionnaire  and  responses  of  each 
investigator. 

The  Commission  brings  this  section  of  its  report  to  con- 
clusion by  a  summary  of  what  it  considers  to  be  the  well- 
ies 


MORBID  ANATOMY  i59 

established  facts  in  the  present  state  of  our  knowledge  con- 
cerning the  pathology  of  epidemic  encephalitis.  It  has  also 
undertaken  to  express  its  opinion  regarding  certain  defects 
in  this  knowledge  and  to  point  out  the  steps  which  may 
be  taken  to  overcome  such  defects. 

The  Gross  and  Microscopic  Pathology  in  the  Ner- 
vous System  (James  B.  Ayer).  Material.  In  a  disease 
of  such  diverse  symptomatology,  and  presenting  so  great 
variations  in  severity  and  duration  of  the  clinical  course, 
it  is  surprising  that  the  pathological  findings  have  been  so 
nearly  uniform. 

The  material  upon  which  the  report  is  based  represents  the 
necropsy  findings  as  published  during  the  period  1917-20 
from  the  following  countries:  Austria  and  Germany,  16 
cases;  Switzerland,  4;  France,  10;  England,  39;  Rumania,  1; 
Canada,  9;  United  States,  34;  a  total  of  113  cases.  The 
reports  from  Australia  have  been  omitted  from  this  sum- 
mary. It  was  surprising  to  find  how  few  pathological  reports 
are  on  record,  considering  the  mortality  of  the  disease,  and 
to  what  extent  the  authors  of  clinical  articles  have  copied  the 
findings  of  a  very  few  investigators.  For  general  description 
all  of  these  113  cases  are  useful,  but  for  fine  histological 
comparison  and  topographic  orientation  a  much  smaller 
number,  not  more  than  50,  is  available. 

Gross  Appearance  of  the  Brain  and  Spinal  Cord.  On  inspec- 
tion the  brain  has  with  few  exceptions  been  found  to  be 
markedly  congested,  at  times  so  intensely  as  to  be  uniformly 
pink  in  color,  both  large  vessels  and  capillaries  being  greatly 
engorged.  Free  blood  is  seen  in  the  sulci,  and  occasionally 
minute  hemorrhages  over  the  gyri,  but  massive  pial  hemor- 
rhage is  seldom  seen.  The  pia-arachnoid  is  frequently  described 
as  edematous.  Rarely  are  the  convolutions  flattened. 
The  dura  mater  has  shown  no  lesion.  If  variation  in  the 
intensity  of  the  meningeal  congestion  has  been  noted  in 
different  loci,  the  most  intense  has  been  over  the  brain  stem, 
and  the  least  over  the  cerebellum.  The  spinal  cord,  when 


i6o 


ACUTE  EPIDEMIC  ENCEPHALITIS 


wholly  removed,  has  frequently  shown  a  similar  vascular  con- 
gestion, always  less  intense  than  that  about  the  mesencepha- 
lon and  fading  out  caudally.  On  section  the  cut  vessels  are 
everywhere  prominent,  both  in  the  brain  and  cervical  cord, 
but  especially  in  the  gray  matter  of  the  basal  ganglia,  mid- 


^5»         '  J  i   . 


•  ^ 


■■£.?  . 


*w£ 


Fig.  io.  Cortical  meninges  from  an  acute  case,  the  patient  dying  sup- 
posedly five  days  after  the  first  symptoms.  Arachnoid  trabecule  sparsely 
infiltrated  with  mononuclear  cells  and  blood  corpuscles.  Pial  vessels  greatly 
engorged.   X  66.  (Wegeforth  and  Ayer,  J.  Am.  M.  Assn.,  July,  19 19,  p.  14.) 


brain  and  pons,  in  which  loci  minute  hemorrhages  are 
occasionally  seen.  The  tissue  is  uniformly  softer  than  normal. 
Ventricles  are  normal  in  size  and  contain  cerebrospinal  fluid 
of  normal  appearance;  the  ependyma  is  usually  smooth  and 
glistening,  but  occasionally  has  been  a  little  roughened. 
Microscopic  Appearance;  Infiltration  and  Hemorrhage. 
Microscopically   the   most   striking   type   of   lesion    is    cell 


MORBID  ANATOMY 


161 


infiltration.  The  vessels  chiefly  affected  are  small  veins,  but 
larger  veins,  arteries  and  capillaries  are  not  immune.  The 
cells  are  almost  always  mononuclear  lymphocytes,  plasma 


Wl*sV:v., 


% 


-  r 
.  •>)*%* 

0 

Fig.  i  i.  Lumbosacral  portion  of  the  spinal  cord  (Case  3).  The  membranes 
are  slightly  infiltrated;  the  subarachnoid  space  shows  on  the  left  a  congested 
vein;  the  anterior  and  posterior  horns  exhibit  a  number  of  infiltrated  vessels; 
the  number  of  ganglion  cells  in  the  anterior  horns  is  normal;  the  ependyma 
cells  of  the  central  canal  are  proliferated  (a  magnifying  hand-glass  will  show 
the  details  better).  (Toluidin-blue  stain,  X  16.)  (Bassoe  and  Hassin,  Arch. 
Neurol.  &  Psycho-Path.,  1919,  ii,  p.  16.) 

and  large  nononuclear  cells,  the  latter  of  doubtful  endo- 
thelial or  mesothelial  origin.  These  cell  infritrations  are 
typically  seen  to  be  confined  to  the  vessel  walls,  the  Virchow- 
Robin  and  perivascular  spaces.  There  is  general  agreement 
11 


1 62 


ACUTE  EPIDEMIC  ENCEPHALITIS 


that  this  type  of  pathological  process  is  most  intense  and 
most  extensive  in  the  gray  matter  of  the  basal  ganglia, 
midbrain,  pons  and  medulla,  and  the  cervical  cord.  The 


>  f     •  *  v     it, 


9S3 


ft        ,    •}  v     jf  '»  «*     i  .  %'  *  /*  .        *  >  .   • 


*# 


>  ■  t,  >** 


&b 


«■ 


V 


&• 


".*.' 


Fig.  12.  Tegmentum  of  pons.  Ag.  Aqueduct  of  Sylvius.  Toluidin  blue, 
X  65.  Three  types  of  lesions  are  shown:  perivascular  infiltration,  diffuse 
infiltration  of  the  nervous  tissue,  and  proliferation  of  the  subependymal 
neuroglia.  (Bassoe  and  Hassin,  Arch.  Neurol,  tf  Psycho-Path.,  1919,  ii,  p.  11.) 

region  about  the  aqueduct  of  Sylvius  is  most  affected  while 
the  severity  of  the  process  lessens  cephalad  and  caudad.  The 
vessels  are  described  as  affected  in  a  patchy  manner,  some 
intensely  infiltrated,  some  normal  in  appearance.  The  vessels 


MORBID  ANATOMY 


163 


of  the  gray  matter  are  chiefly  involved  while  those  of 
the  white  are  by  no  means  immune.  In  the  same  territory, 
and  frequently  in  apparent  connection  with  the  above 
described  infiltration,  occurs,  in  almost  every  case,  the  second 
most  striking  type  of  lesion,  namely,  diffuse  infiltration  of 
the  nervous  tissues.  The  same  types  of  cells  are  here  seen 
scattered  through  and  intermingling  with  the  fixed  cells  and 


•a,  ,'.  ^» 


'* 

Fig.  13.  Hemorrhage  into  the  perivascular  space  of  His,  region  of  thalamus. 
This  is  the  type  oi  hemorrhage  commonly  observed  in  this  disease.  (Tilney  and 
Riley,  Neurol.  Bull.,  19 19,  ii,  p.  127.) 

fibers  constituting  gray  and  white  matter.  Not  infrequently 
large  mononuclear  phagocytes  are  found  in  these  terri- 
tories, and  with  special  stains  free  fat  droplets  are  here 
visible.  This  diffuse  infiltrative  process  is  usually  described 
as  being  most  intense  in  and  near  the  substantia  nigra. 
It  is  interesting  and  important  to  note  that,  with  rare 
exception,  polymorphonuclear  leucocytes  are  not  present. 
Hemorrhage,  as  has  been  stated,  is  not  regularly  noted 
in  the  gross  appearance.  Microscopically,  hemorrhage  into 


164 


ACUTE  EPIDEMIC  ENCEPHALITIS 


the  perivascular  space  of  His  is  seen  frequently;  rarely, 
however,  does  it  spread  from  this  locus  into  the  nervous 
tissue.  While  hemorrhage  may  occur  from  vessels  showing 


&& 


' 


m-^9' 


* 


Fig.  14.     Midbrain,  X  720:  diffuse  infiltration  with  plasma  cells  and  lympho- 
cytes. (Wegeforth  and  Ayer,  J.  Am.  M.  Assn.,  July,  19 19,  p.  21.) 

perivascular  cell  infiltration,  this  is  not  necessarily  so.  Nor 
is  hemorrhage  associated  with  any  marked  degree  of  vascular 
disease,  as  indicated  by  minimal  changes  in  the  intima  and 
elastica,  and  almost  total  absence  of  thrombosis  during  the 


MORBID  ANATOMY 


165 


acute  state  of  the  disease.  Where  hemorrhage  into  the  par- 
enchyma is  seen,  it  is  usually  not  accompanied  by  reaction 
of  the  surrounding  glia. 


Fig.  15.  Midbrain,  X1060.  Mononuclear  phagocytes  and  plasma  cells  in 
white  matter.  Death  twenty-nine  days  from  onset  of  symptoms.  (Wegeforth 
and  Ayer,  J.  Am.  M.  Assn.,  July,  1919,  p.  23.) 

Changes  in  the  Nerve  Cells  and  Neuroglia.  In  discussing 
changes  in  the  nervous  tissue  itself,  nerve  cells,  nerve  fibers 
and  neuroglia,  there  is  considerable  difference  of  opinion. 
This  is  but  natural,  considering  the  difficulty  in  adequately 
estimating  abnormalities  of  these  structures.  The  majority 


1 66 


ACUTE  EPIDEMIC  ENCEPHALITIS 


of  writers  evidently  have  not  studied  these  tissues  with  thor- 
oughness; hence  our  knowledge  of  parenchymatous  lesions 
depends  upon  the  reports  of  a  very  few  careful  workers. 

The  nerve  cells  unquestionably  show  relatively  little 
evidence  of  degeneration  considering  the  severity  of  the 
pathological  process.   Intense  generalized  destructive  pro- 


Fig.  1 6.  A  destroyed  ganglion  cell  from  the  subthalamic  region  surrounded 
by  plasma  cells.  (Toluidin  blue,  X  1200.)  Neurophagia  is  absent  in  many  of  the 
cases  reported;  it  is  more  likely  to  be  seen  in  cases  of  several  weeks  duration. 
(Bassoe  and  Hassin,  Arch.  Neurol.  &  Psycho-Path.,  1919,  ii,  p.  14.) 


cesses  throughout  the  brain  or  the  spinal  cord  have  not  been 
described,  and  only  rarely  have  focal  degenerations  of  large 
extent,  as  seen  in  certain  other  types  of  encephalitis,  been 
observed.  In  areas  of  greatest  inflammation,  nerve  cells 
appear  apparently  intact  in  the  midst  of  extensive  mono- 
nuclear cell  infiltrations.  In  the  neighborhood  of  such  terri- 
tories minor  changes,   such  as   chromatolysis,   are  usually 


MORBID  ANATOMY 


167 


described.  However,  isolated  examples  of  cell  destruction, 
chromatolysis,  swelling  of  the  cell,  excentricity  of  the  nucleus, 
absence  of  neurofibrils,  satellitosis,  and  even  neuronophagia 
are  described  in  areas  of  intense  infiltrations.  In  territory 
free  from  the  striking  changes  of  the  disease,  such  as  the 
cerebral  cortex  and  cerebellum,  nerve  cells  of  all  types  are 
usually  found  to  be  normal  or  to  present  minimal  degenera- 


"0  «      ,.'tn,:  • 


**HL 


Fig.  17.  Hypoglossal  nucleus.  Many  of  the  nerve  cells  appear  normal, 
but  some  are  degenerated.  The  nucleus  was  infiltrated  with  ameboid  glia 
cells.  (Tilney  and  Riley,  Neurol.  Bull.,  1919,  ii,  p.  127.) 


tive  changes;  however,  complete  degeneration  of  the  smaller 
pyramidal  cells  and  of  Purkinje  cells,  with  or  without 
neuronophagia,  occurs. 

Neuroglia  cell  proliferation  is  said  to  be  very  considerable 
in  and  about  areas  of  intense  cellular  invasion,  and  about 
vessels  presenting  marked  perivascular  infiltration.  In  the 
cortex  and  subcortex,  also,  diffuse  neuroglia  proliferation  of 
the  small  cell  type  is  evident  in  proportion  to  the  amount  of 
nerve  cell  destruction.  Multinuclear  forms  are  not  described, 


1 68 


ACUTE  EPIDEMIC  ENCEPHALITIS 


nor  is  there  evidence  of  neuroglia  fibril  formation  on  a  scale 
to  warrant  comment. 

Microscopic  Changes  in  the  Meninges.     Pia  and  arachnoid 
may  be  normal.  Usually,  however,  besides  greatly  engorged 


Fig.  i 8.  Pial  vessels  during  the  acute  stage.  (Resorcin-fuchsin,  X  60).  The 
elastic  membrane  in  the  form  of  solid  rings  is  very  clear.  In  the  acute  stage  the 
intima  also  is  normal  or  only  slightly  affected,  vascular  lesions  being  almost 
confined  to  the  adventitia.  (Bassoe  and  Hassin,  Arch.  Neurol.  &  Psycho-Path., 
1919,  ii,  p.  7.) 

vessels,  already  noted  in  the  naked  eye  examination,  the 
layers  of  the  pia  and  the  reticular  network  of  the  arachnoid 
are  separated  and  in  the  interstices  are  numerous  red  cor- 
puscles and  large  mononuclear  cells.  In  the  depths  of  the 
sulci  intrapial  extravasations  of  red  corpuscles  are  occasion- 


MORBID  ANATOMY 


169 


ally  observed.  Except  in  these  latter  areas  polymorphonuclear 
leucocytes  are  lacking. 

Summary.  The  locus  of  the  most  intense  reaction  is  a  mat- 
ter of  general  agreement.  The  brain-stem  bears  the  brunt  of 
the  attack  in  almost  every  case.  That  the  gray  matter  in  gen- 


Fig.  19.  Basal  ganglia.  Medium-sized  vein  showing  thrombosis  and 
calcareous  degeneration  of  its  walls.  (Zeiss  16  mm.  obj.  Comp.  ocular  No.  4.) 
From  a  case  dying  four  months  following  the  acute  attack.  The  patient  was  a 
young  woman,  and  it  is  unlikely  that  the  lesions  in  the  vessels  which  were 
widespread  should  be  attributed  to  other  cause  than  the  preceding  encepha- 
litis. (Buzzard  and  Greenfield,  Brain,  19 19,  xlii,  p.  330.) 


eral  is  the  seat  of  greatest  inflammation  is  certain,  but  that 
the  cranial  nerve  nuclei  are  especially  affected  has  not  been 
apparent  in  all  cases.  The  inflammatory  process  is  not  by  any 
means  limited  to  the  gray  matter,  either  of  the  brain  or 
spinal  cord. 

There  is  agreement  that  the  pathologic  process  concerns 
primarily   mesodermal   structures,   that   infiltration  of  the 


i7o  ACUTE  EPIDEMIC  ENCEPHALITIS 

smaller  vessel  walls  and  their  true  perivascular  spaces  by 
lymphocytes,  plasma  cells  and  large  mononuclear  cells  is 
constant;  that  diffuse  infiltration  of  the  gray  matter  chiefly, 
but  also  of  the  white,  is  usually  present.  Also  constant,  but 
less  striking,  are  changes  in  the  ectodermal  tissues,  degenera- 
tive changes  in  the  parenchymatous  elements,  with  associ- 
ated proliferation  of  neuroglia  cells.  The  changes  observed 
in  nerve  cells  and  neuroglia,  while  most  intense  in  areas  of 
infiltration,  may  also  be  seen  apart  from  any  inflammatory 
foci.  There  is  agreement  also  that  the  blood-vessels,  while 
universally  engorged,  remain  relatively  intact  (until  very 
late  in  the  disease),  as  evidenced  by  almost  total  absence  of 
large  or  frequent  hemorrhages,  thromboses  and  microscopic 
evidence  of  degenerative  or  proliferative  processes  in  their 
walls.  The  meningeal  reaction  is  also  constantly  minimal 
in  degree. 

Microscopical  Changes  in  Nerve  Roots,  Cranial  Nerves  and 
Dorsal  Root  Ganglia.  Examination  of  the  cranial  nerve 
roots  has  been  carried  out  especially  by  Burrows.  In  each  of 
three  cases  (two  of  them  typically  lethargic  and  one  poly- 
neuritic) he  found  lesions  in  several  of  the  cranial  nerves, 
the  2nd,  4th,  5th,  6th,  7th,  8th  being  affected.  The  lesion  is 
described  as  a  perivascular  lymphocytic  infiltration  and  an 
interstitial  infiltration  of  the  nerve  fibers  by  lymphocytes. 
Perivascular  infiltration  of  the  optic  nerve  was  observed  by 
Mills  and  Wilson  and  of  the  12th  nerve  by  the  writer. 

There  is  almost  nothing  written  on  the  subject  of  spinal 
nerve  roots  and  root  ganglia,  an  omission  of  importance  in 
view  of  the  fact  that  in  poliomyelitis  the  ganglia  so  fre- 
quently show  marked  changes. 

Microscopical  Changes  in  Cases  oj  Long  Duration.  A  case 
of  four  months'  duration  reported  by  Buzzard  and  Green- 
field showed  marked  change  in  the  pathological  picture. 
The  vessels  had  irregularly  thickened  walls,  frequently  with 
calcareous  plaques.  The  lumen  was  often  closed  by  fibrous 
or  fibrinous  occlusions.  This  was  true  of  the  vessels  of  the 
cortex  and  meninges  as  well  as  of  those  of  the  brain-stem. 


MORBID  ANATOMY  171 

Neuroglial  proliferation  was  marked.  Perivascular  cell  infil- 
tration was  likewise  present  and  the  nerve  cells  showed  a 
minimal  amount  of  damage. 

Von  Economo  has  published  the  report  of  a  patient  dying  a 
year  and  nine  months  after  the  onset  of  the  illness.  In  this 
case  the  vessels  showed  thickened  walls  and  thrombi,  and 
the  neuroglial  proliferation  was  marked. 

Pathology  in  Relation  to  Clinical  Types  of  the  Dis- 
ease. With  the  original  conception  based  upon  the  first  de- 
scribed cases  of  von  Economo  and  Netter,  lethargic  encephali- 
tis must  necessarily  be  accompanied  by  lethargy,  oculomotor 
palsy  and  perhaps  other  cranial  nerve  affection,  and  a  patho- 
logic picture  was  presented  which  was  considered ,  pathog- 
nomonic. It  was  not  long  before  cases  with  very  different 
clinical  picture  presented  themselves — epileptiform,  chorei- 
form, hemiplegic,  polyneuritic  forms.  One  would  a  priori 
think  that  entirely  different  pathological  lesions,  both  as  to 
type  and  as  to  distribution,  would  be  required  to  account 
for  such  diverse  and  contrasting  clinical  pictures.  On  the 
contrary,  examinations  of  the  records  of  published  cases, 
including  most  if  not  all  of  the  clinical  types  of  epidemic 
encephalitis,  fail  to  show  great  variation  in  pathology. 
Certain  irregularities  as  to  distribution  do  occur,  but  it 
appears  that  the  same  pathological  lesions  varying  some- 
what in  proportion  are  constant  findings.  So  that  whatever 
the  clinical  type,  the  pathological  picture  described  in  the 
first  section  of  this  paper  is  pretty  certain  to  be  found  with 
modifications  only  as  to  intensity  and  locality  of  the  different 
types  of  lesions. 

Certain  of  the  clinical  findings  and  clinical  types  of  the 
disease  are  readily  explained  on  the  basis  of  the  pathological 
changes  noted.  The  cranial  nerve  palsies  occurring  in  the 
common  forms  of  the  disease  are  readily  explained  by  the 
marked  infiltration  in  the  nuclei,  with  or  without  destruction 
of  nerve  cells;  in  some  cases  a  second  possible  explanation 
for  the  palsy  has  been  shown  in  the  infiltration  of  the  nerves 


172  ACUTE  EPIDEMIC  ENCEPHALITIS 

themselves.  In  the  hemiplegic  and  apoplectic  forms,  conflu- 
ent petechial  hemorrhages,  either  in  the  subcortex  (Buzzard 
and  Greenfield,  2  cases;  Boyd,  1  case),  or  in  the  peduncle 
(Wilson)  have  adequately  accounted  for  the  symptoms. 
Cases  with  excessive  meningeal  symptoms  have  been  shown 
to  reveal  profound  congestion,  frequently  with  considerable 
pial  hemorrhage,  and  at  times  excessive  mononuclear  cell 
infiltration  of  the  pia  (Da  Fano,  Neal,  Schwartz).  The  an- 
terior poliomyelitic  forms  have  been  adequately  explained 
by  appropriately  placed  inflammatory  reactions  in  the  spinal 
cord  (Calhoun). 

While  necropsies  on  psychotic,  choreopsychotic,  delirious, 
catatonic,  myoclonic  and  paralysis  agitans  types  have  been 
recorded,  and  some  of  the  reports  are  carefully  prepared, 
there  is  not  enough  distinctive  in  them  to  warrant  drawing 
conclusions  as  to  the  explanation  of  the  peculiar  symptoms. 
In  fact,  any  of  these  reports  might  pass  as  descriptive  of  a 
typical  lethargic  case.  Most  reports  have  evidently  been  com- 
piled with  no  especial  reference  to  a  pathological  explanation 
of  clinical  syndromes.  But  even  when  this  has  been  attempted 
no  distinctive  differences  appear  to  have  been  encountered. 
For  example,  Bassoe,  commenting  on  the  pathology  of  two 
personal  cases  of  the  delirious  type,  says:  "It  will  be  noted 
that  essentially  the  changes  are  the  same  as  in  the  ordinary 
lethargic  form." 

The  following  questions  submitted  to  Dr.  Ayer  before  the 
Commission,  together  with  the  answers  to  them,  are  here 
reported  verbatim. 

Dr.  Sachs:  May  I  question  Dr.  Ayer  especially  with  reference 
to  one  statement  which  he  made,  which  I  think  was  a  striking  one? 
I  think  we  ought  to  ask  whether  any  gentleman  here  has  had 
autopsy  findings  in  these  cases  and  whether  we  are  actually  going 
to  accept  it  as  a  fact  that  in  this  disease  the  cortex  is  the  part 
least  involved. 

Dr.  Ayer:  That  has  been  universally  so.  I  have  not  seen  a 
single  case  where  the  cortex  was  said  to  be  involved  as  much 


MORBID  ANATOMY  173 

as  any  other  part,  and  it  is  always  involved  very  much  less;  in 
many  cases  the  cortex  is  negative.  I  would  like  to  qualify  that 
remark  a  little.  The  cases  are  not  always  differentiated  patholog- 
ically, but  all  types  have  fallen  under  the  pathological  hammer. 
One  would  expect  to  get  more  cortical  changes  relatively,  but  this 
has  not  been  the  case.  With  all  the  types  that  may  have  died  from 
bulbar  lesions  taken  into  account,  they  all  look  about  the  same 
and  there  is  little  to  choose  in  them. 

Dr.  Sachs  :  The  important  inference  would  be  that  the  Iethargy 
has  nothing  to  do  with  the  cortex. 

Dr.  Ayer:  That  is  one  problem  that  might  be  called  physio- 
logical pathology,  perhaps.  We  do  not  know  much  about  it. 
There  is  this  tremendous  engorgement  of  the  vessels,  and  many 
of  the  symptoms,  such  as  delirium,  may  be  due  to  pure  engorgement 
of  the  vessels.  That  is  a  thing  we  have  no  means  of  checking  up. 
And  so  this  fluid  state — the  cerebrospinal  fluid  and  the  blood — 
may  play  a  large  part  which  when  we  look  at  it  pathologically, 
we  cannot  judge.  All  we  can  say  is  that  in  every  case  the  one 
thing  that  stands  out  is  the  engorgement  of  all  vessels  especially 
at  the  base  of  the  brain. 

Dr.  Tilney:  Is  it  not  also  true  that  the  investigation  of  the 
cortex  has  been  thoroughly  inadequate  and  will  not  justify  any 
comparative  statement  at  the  present  time?  Merely  pieces  of 
cortex  have  been  taken  here  and  there,  and  we  can  not  guarantee 
any  statement  as  to  the  relative  cortical  involvement. 

Dr.  Ayer:  As  a  rule  one  or  two  pieces  are  examined,  and  then 
the  cortex  is  put  down  as  negative.  Very  few  articles  have  really 
as  yet  adequately  covered  the  whole  brain. 

Dr.  Prince:  Has  serous  infusion  in  ventricles  ever  been  found? 

Dr.  Ayer:  The  ventricles  almost  always  have  been  normal  in 
size  and  have  been  found  to  contain  the  normal  amount  of  fluid. 

Detailed  Pathological  Report  of  the  Brains  of 
Five  Cases  and  the  Spinal  Cord  from  Two  of  These 
Cases  (William  G.  Spiller).  Changes  in  the  Cerebral 
Cortex.  The  pathological  changes  in  the  paracentral  lobules 
were  slight  in  all  five  cases;  there  was  slight  infiltration  of  the 
pia  with  mononuclear  cells,  and  some  of  the  Betz  cells  showed 
distinct  chromatolysis,  but  in  most  of  the  cases  these 
cells  could  hardly  be  considered  abnormal,  especially  as  the 


174  ACUTE  EPIDEMIC  ENCEPHALITIS 

necropsies  were  not  done  very  soon  after  death  and  formalin 
hardening  was  employed.  There  was  little  infiltration  of  the 
cortex  with  mononuclear  cells.  Neuronophagia  was  distinct. 
On  the  whole  the  changes  might  be  regarded  as  relatively 
insignificant.  The  findings  in  other  parts  of  the  cerebral 
cortex  were  similar. 

Changes  in  the  Basal  Ganglia.  The  basal  ganglia  were 
examined  in  their  lower  portion.  Much  infiltration  with 
mononuclear  cells  of  lymphocytic  type  and  plasma  cells  was 
found  in  all  five  cases,  and  the  collections  of  cells  were 
greater  in  some  places  than  in  others.  In  two  cases  the 
infiltration  was  less  than  in  the  other  three,  and  one  of  these 
two  was  a  case  of  the  myoclonic  type.  The  condition  was 
like  that  in  the  cerebral  peduncles  but  was  less  intense.  In  one 
case  the  ependymal  cells  showed  an  extraordinary  appear- 
ance in  one  place;  they  were  proliferated  and  massed  one 
upon  another.  The  infiltration  in  the  case  of  the  myoclonic 
type  was  diffuse  and  not  nearly  so  intense  as  in  some  other 
cases. 

Changes  in  the  Cerebral  Peduncles.  In  four  cases  the  lesions 
in  the  cerebral  peduncles  were  intense,  but  they  were  slight 
in  this  region  in  the  case  of  the  myoclonic  type.  The  intense 
infiltration  of  lymphocytes  and  plasma  cells  was  not  only 
about  the  vessels  but  in  the  tissue  where  no  vessels  could  be 
seen,  also  in  the  pia  between  the  crura  and  especially  about 
the  pial  vessels,  but  not  in  the  crura.  These  escaped  almost 
entirely  although  the  infiltration  in  the  tegmentum  came 
close  to  the  crura.  This  explains  the  absence  of  paralysis  of 
the  limbs.  The  nerve  cells  near  the  aqueduct  including  those 
of  the  oculomotor  nucleus  on  each  side  showed  considerable 
chromatolysis,  but  little  displacement  of  their  nuclei.  The 
cellular  infiltration  was  by  no  means  confined  to  the  area 
about  the  aqueduct.  Small  hemorrhages  occurred  but  were 
not  intense. 

In  one  case  a  small  area,  oval  and  sharply  defined  from  the 
surrounding  tissue,  of  a  light  brown  color  by  the  Weigert 
hematoxylin  stain,  was  found  just  above  the  innermost  part 


MORBID  ANATOMY  175 

of  the  substantia  nigra.  In  a  nuclear  stain  this  area  was  seen 
to  consist  of  loose  glial  tissue  from  which  the  nerve  fibers  had 
disappeared,  leaving  small  holes.  This  area  contained  many 
large  cells  with  large  nuclei,  probably  they  were  the  corps 
granuleux  (fatty  granular  cells).  This  area  represented  the 
late  stage  of  a  focus  of  inflammation  and  resembled  by  its 
appearance  and  sharp  delimitation  in  a  striking  degree  one 
of  the  sclerotic  patches  by  the  Weigert  stain  in  a  case  of 
multiple  sclerosis.  Only  one  such  sclerotic  patch  was  found 
and  in  only  one  case,  but  its  discovery  suggested  the 
possibility  of  multiple  sclerosis  developing  after  epidemic 
encephalitis. 

It  seems  remarkable  that  only  in  the  case  of  the  myoclonic 
type  little  cellular  infiltration  was  found  in  the  cerebral 
peduncles.  It  is  believed  that  this  condition  will  be  deter- 
mined in  all  cases  of  the  myoclonic  type.  There  was  some 
lymphocytic  infiltration  near  the  aqueduct  but  the  intense 
perivascular  infiltration  of  the  other  cases  was  absent. 
The  cerebral  peduncles  were  affected  in  a  case  of  the  myo- 
clonic type  studied  by  Winkelman. 

Changes  in  the  Pons,  Medulla  and  Cerebellum.  The 
findings  in  the  pons  and  medulla  were  similar  to  those  in  the 
cerebral  peduncles,  and  it  is  noteworthy  that  they  were 
intense  in  this  region  in  the  case  of  the  myoclonic  type,  as 
well  as  in  the  others,  and  much  more  severe  here  in  the  myo- 
clonic case  than  in  the  cerebral  peduncles.  The  infiltration 
was  especially  intense  near  the  floor  of  the  fourth  ventricle, 
and  this  probably  explains  the  sudden  death  with  bulbar 
symptoms  so  common  in  this  disease,  which  also  occurred 
in  the  case  of  the  myoclonic  type.  The  pyramids  and  pia 
were  little  affected.  Very  little  alteration  was  found  in  the 
cerebellum. 

Changes  in  the  Spinal  Cord.  The  spinal  cord  was  obtained 
in  two  cases  only,  and  unfortunately  not  in  the  case  of  the 
myoclonic  type.  In  one  of  the  two  cases  the  cervical  region 
was  missing.  Moderate  infiltration  of  lymphocytes  and 
plasma  cells  was  found  in  the  pia  and  about  the  vessels  of  the 


176  ACUTE  EPIDEMIC  ENCEPHALITIS 

cord  substance,  and  also  at  some  places  within  the  cord 
without  apparent  association  with  a  vessel.  The  nerve  cells 
of  the  anterior  horns  did  not  show  any  pronounced  altera- 
tion. In  one  case  there  was  an  extraordinary  number  of 
corpora  amylacea  in  the  thoracic  region,  and  the  patient 
was  not  advanced  in  years. 

The  noteworthy  finding  in  this  study  was  the  slight 
involvement  of  the  cerebral  peduncles  in  the  case  of  the 
myoclonic  type  when  the  medulla  oblongata  showed  severe 
cellular  infiltration  and  the  basal  ganglia  also,  though  less 
severe  than  the  medulla  oblongata.  Sudden  death  occurred 
in  this  case.  Also  the  area  of  degeneration  in  one  case  resem- 
bling that  of  multiple  sclerosis;  the  peculiar  heaping  up  of 
ependymal  cells  in  one  case;  the  escape  of  the  pyramidal 
tract  in  all  the  cases,  and  the  slight  implication  of  the 
cerebral  cortex.  In  no  case  were  there  found  extensive  hem- 
orrhages such  as  have  been  seen  in  other  forms  of  inflamma- 
tion of  the  central  nervous  system. 

The  following  questions  submitted  to  Dr.  Spiller  before  the 
Commission,  together  with  the  answers  to  them,  are  here 
reported  verbatim. 

Dr.  Tilney:  In  selecting  the  paracentral  lobules,  was  there 
any  special  reason  for  confining  the  examination  of  the  cortex 
to  that  part  of  the  brain? 

Dr.  Spiller:  No,  only  that  the  paracentral  lobules  are  the 
most  satisfactory  for  routine  study  and  I  have  always  taken  them 
for  that  purpose.  They  contain  the  largest  nerve  cells  of  the  human 
body,  are  the  easiest  to  study,  and  give  us  more  conclusive  evidence 
as  to  what  the  findings  may  be. 

Dr.  Tilney:  Did  the  medullary  substance  show  any  changes? 

Dr.  Spiller:  No;  not  anything  very  significant;  the  findings 
were  rather  insignificant.  I  do  not  know  any  reason  why  I  should 
not  say  that  it  was  Dr.  Copeland  who  took  a  piece  of  this  brain, 
could  not  find  anything  that  was  very  striking,  and  thought  it 
was  not  a  case  of  epidemic  encephalitis.  He  told  me,  and  other 
well  known  pathologists  told  me,  in  another  case  they  found  in  the 
kidneys  quite  sufficient  to  explain  the  symptoms,  but  the  lesions 


MORBID  ANATOMY  177 

in  those  two  cases  in  the  basal  part  of  the  brain  were  as  typical 
as  anyone  could  wish  to  see. 

Dr.  Tilney:  Nearly  everyone  has  made  some  statement  in 
reference  to  chromatolysis.  The  degree  of  chromatolysis  seems 
to  be  a  point  of  debate. 

Dr.  Spiller:  I  think  chromatolysis  is  debatable  under  all 
circumstances.  When  the  matter  of  chromatolysis  first  came  out  in 
the  literature  of  twenty-five  or  thirty  years  ago,  I  remember 
working  in  a  laboratory  and  being  shown  changes  in  the  nerve 
cells  which  were  gotten  in  nicotine  and  strychnine  and  various 
forms  of  intoxication.  When  you  consider  the  methods  of  harden- 
ing— these  were  not  done  immediately  after  death — one  must 
be  extremely  cautious  in  accepting  any  judgment  in  regard  to 
these  final  cell  changes.  Chromatolysis  occurs  so  very  readily. 
I  do  not  think  it  is  a  post-mortem  change,  but  one  must  not 
attribute  too  much  to  chromatolysis.  I  did  not  find  in  any  of 
these  the  blowing  up  of  the  cells  or  the  marked  eccentric  position 
of  the  nucleus— none  of  those  changes  which  are  so  very  striking 
and  of  so  great  pathological  importance. 

Dr.  Tilney:  With  relation  to  the  hemorrhages  described,  were 
they  entirely  extravascular,  perivascular  or  in  the  Virchow-Robin 
spaces? 

Dr.  Spiller:  They  were  around  the  vessels  and  in  the  vessel 
walls.  They  were  never  very  numerous  or  intense  in  the  sections 
I  had  an  opportunity  of  studying,  and  did  not  get  out  into  the 
tissue  very  much. 

Dr.  Tilney:  Did  the  sclerotic  patch  described  in  the  cerebral 
peduncle  have  many  features  in  common  with  patches  of  multiple 
sclerosis? 

Dr.  Spiller:  It  looked  exceedingly  like  multiple  sclerosis, 
and  when  I  examined  it  with  an  acid  stain  which  characterized 
these  patches  so  clearly  in  multiple  sclerosis,  I  could  not  have  told. 
Even  under  a  nuclear  stain  it  had  the  appearance  of  a  sclerotic 
patch.  But  we  cannot  conclude  that  such  a  patch  is  going  to 
proliferate  or  is  going  to  produce  further  symptoms.  I  look  upon 
it  as  a  scar  and  I  would  not,  therefore,  attribute  too  much  to  it. 
If  such  a  patch  or  such  patches  are  found  in  other  cases,  they 
will  have  very  great  significance.  There  is  a  possibility  that 
following  epidemic  encephalitis  these  patches  from  areas  where 
there  has  been  intense  infiltration  may  become  numerous,  and 
12 


178  ACUTE  EPIDEMIC  ENCEPHALITIS 

possibly  even  the  neuroglia  may  proliferate  and  we  may  have, 
though  I  have  not  seen  any  such  cases  nor  heard  of  them,  a  typi- 
cal picture  of  disseminated  sclerosis  resulting  from  lethargic 
encephalitis. 

Dr.  Tilney:  Is  it  your  opinion  that  there  is  any  possible  relation 
of  epidemic  encephalitis  to  multiple  sclerosis? 

Dr.  Spiller:  I  do  not  know  of  any  relation  between  them. 
The  subject  of  multiple  sclerosis  is  now  undergoing  somewhat  of 
a  change  in  regard  to  our  opinions  of  it.  In  the  past  few  years 
I  have  reported  a  case  where  there  was  certainly  a  proliferation 
of  the  neuroglia,  and  I  could  not  believe  in  a  view  formerly  held 
that  it  was  merely  the  replacement  of  destroyed  tissue.  It  was 
certainly  an  active  process  going  on.  I  could  see  where  these 
new  neuroglia  cells  like  an  advancing  army  were  going  into  the 
more  nearly  normal  tissue  of  the  brain.  In  the  spinal  cord  the 
lesions  were  more  advanced  and  there  was  nothing  of  that.  No 
human  being,  I  venture  to  say.  could  have  seen  in  the  spinal  cord 
anything  differing  from  any  ordinary  case  of  multiple  sclerosis; 
but  in  the  brain  it  was  certainly  the  neuroglia  in  the  active  state. 
I  see  no  direct  connection  whatever  between  multiple  sclerosis 
and  epidemic  encephalitis. 

Dr.  Hunt:  Are  there  any  lesions  in  the  nerve  roots  to  explain 
the  radicular  types  ol  the  disease? 

Dr.  Spiller:  In  regard  to  the  involvement  of  the  root,  how 
can  the  cervical  nerves  escape  if  all  about  them  is  infiltrated  with 
cells?  They  are  involved  more  or  less,  but  I  have  not  had  enough 
cases  to  study  in  which  the  spinal  cord  was  affected.  I  have  not 
seen  sufficient  indications  in  the  spinal  cord  roots  to  justify  any 
conclusions  of  decided  infiltration  of  the  roots  of  the  spinal  cord. 

Dr.  Sachs:  It  is  conceded  that  there  are  no  large  hemorrhages 
in  these  cases,  but  I  would  like  to  ask  Dr.  Spiller  whether  he 
would  recognize  a  distinct  difference  between  these  cases — this 
process  and  the  process  we  formerly  acknowledged  to  be  the  pro- 
cess of  acute  hemorrhagic  and  acute  encephalitis? 

Dr.  Spiller:  No,  because  I  think  these  cases  are  sometimes 
spoken  of  as  acute  hemorrhagic  and  acute  encephalitic.  I  reported 
a  number  of  years  ago  a  case  of  myoclonic  type  of  poliomyelitis 
where  the  hemorrhages  in  the  anterior  horns  were  very  numerous, 
that  I  should  regard  as  a  type  of  hemorrhagic  infiltration,  but 
in  these  *cases_the  hemorrhages  had  to  be  hunted  for  in  order  to 


MORBID  ANATOMY  179 

be  found.  They  did  not  strike  the  eye  on  first  looking  at  the 
sections.  They  were  small  collections  of  red  blood  corpuscles. 

Dr.  Taylor  :  Admitting  neuronophagia,  is  there  any  fundamental 
difference  then  except  in  degree  between  this  lesion  and  the  lesion 
of  poliomyelitis? 

Dr.  Spiller:  A  most  interesting  subject.  I  really  would  be 
in  great  doubt  if  I  had  a  section  presented  to  me.  I  think  some- 
times clinically  we  are  in  great  doubt.  I  had  a  patient  who  came 
from,  the  coast  of  Maine  at  the  time  there  was  an  outbreak,  and  I 
thought  it  was  a  case  of  lethargic  encephalitis;  later  I  began  to 
believe  it  was  poliomyelitis  of  the  basic  gangliar  type.  I  believe 
you  do  not  get  in  the  spinal  cord  the  changes  in  encephalitis 
that  you  get  in  poliomyelitis,  and  you  have  a  point  of  distinction. 
But  if  you  take  a  section  of  what  you  suspect  to  be  a  basilar 
form  of  poliomyelitis,  I  do  not  see  how  under  the  microscope  you 
could  say  positively  it  was  a  case  of  lethargic  encephalitis  and 
not  poliomyelitis.  I  myself  would  not,  I  am  sure. 

Dr.  Patrick:  You  say  that  in  the  case  of  acute  bulbar  paralysis 
you  could  not  tell  it  in  looking  at  the  section.  Could  you  distinguish 
it  from  poliomyelitis? 

Dr.  Spiller:  You  would  expect  to  find  changes  in  the  spinal 
cord  which  are  characteristic  in  the  acute  cases.  In  looking  merely 
at  the  bulbar  part,  I  should  not  be  able  to  tell  it,  I  am  afraid. 

Dr.  Taylor:  Does  it  not  bring  us  back  to  the  original  idea 
that  encephalitis  and  poliomyelitis  are  presumably  due  to  the 
same  cause  and  are  essentially  the  same  lesion  with  different 
localizations?  It  seems  we  are  going  back  to  the  original  idea. 
In  other  words,  are  we  not  making  again  unnecessary  distinctions 
between  these  lesions  which  may  be  essentially  the  same,  simply 
differing  in  localization  rather  than  in  kind? 

Dr.  Spiller:  There  is  a  great  deal  in  that  idea,  and  yet  from 
investigations  of  Dr.  Strauss  and  his  co-workers  there  are  going 
to  be  other  means  of  establishing  that  the  two  diseases  are  not 
necessarily  the  same  thing  simply  because  the  lesions  resemble 
one  another.  Histologically,  they  are  certainly  very  close. 

Dr.  Prince:  In  rapid  cases  what  is  the  common  cause  of  death? 

Dr.  Spiller:  In  one  case  a  man  came  to  me  who  had  the  myo- 
clonic twitchings  and  jerkings.  I  thought  he  was  in  no  particular 
danger  and  was  probably  going  to  get  well.  I  was  startled  to  hear 
when  I  went  to  the  office  the  next  morning  that  he  had  died  at 


180  ACUTE  EPIDEMIC  ENCEPHALITIS 

five  o'clock.  I  found  that  his  medulla  oblongata  was  the  seat 
of  intense  infection,  and  I  am  inclined  to  think  these  sudden 
deaths  are  due  to  the  involvement  of  the  medulla  oblongata. 

Dr.  Prince:  What  is  the  common  cause  in  general  though  in 
rapid  cases? 

Dr.  Spiller:  I  should  attribute  these  sudden  deaths  almost 
invariably  to  the  oblongata.  It  is  hard  to  answer  that  otherwise. 
The  complication  is  there.  In  a  number  of  these  cases  there  are 
serious  kidney  troubles,  and  I  do  not  know  if  it  is  not  from  the 
kidneys.  I  should  not  be  able  to  answer  that. 

Dr.  Ladd:  Did  you  note  any  difference  between  the  pathology 
of  the  venules  and  arterioles? 

Dr.  Spiller:  That  is  a  point  emphasized  a  great  deal  by 
foreign  writers.  It  has  been  generally  acknowledged  that  the  veins 
are  more  involved  than  the  arterioles.  It  is  not  always  easy  in 
a  small  arteriole  to  say  positively  whether  it  is  a  vein  or  arteriole. 
I  have  had  dfficulty  in  determining  that. 

Changes  in  the  Endocrine  System  (Hubert  S.  Howe). 
Histological  examination  of  the  glands  of  internal  secretion 
in  epidemic  encephalitis  was  undertaken  to  ascertain  if  any 
alterations  were  to  be  found,  and  if  so  whether  they  had  any 
bearing  on  the  course  or  manifestations  of  the  disease.  The 
material  consists  of  four  cases  that  were  under  observation 
prior  to  death.  The  autopsies  were  made  shortly  after  death. 
The  material  was  fixed  in  Zencker's  solution  and  the  blocks 
imbedded  in  paraffin.  Sections  were  stained  with  hematoxy- 
lin and  eosin. 

Histological  examination  was  made  of  the  thyroid  gland, 
adrenals,  the  pituitary  body,  gonads  and  pancreas. 

THE    THYROID    GLAND 

Case  I.  The  alveoli  were  of  all  sizes  and  filled  with  colloid. 
The  lining  epithelium  was  cuboidal.  There  was  very  little  inter- 
stitial tissue  and  in  places  this  appeared  hyalinized  or  even  colloid- 
like. In  the  interstitial  tissue  were  a  few  localized  collections  of 
small  cells  with  dense  pyknotic  nuclei.  The  vessels  were  greatly 
congested. 


MORBID  ANATOMY  181 

Case  II.  The  thyroid  was  small,  soft  and  symmetrical,  and 
grossly  normal.  Microscopical  examination  showed  the  vesicles 
of  average  and  about  uniform  size,  filled  with  pinkish  staining 
colloid.  The  cells  were  cuboidal  and  for  the  most  part  lined  the 
acini  in  single  rows.  The  blood-vessels  were  not  congested. 

Case  III.  The  thyroid  was  of  normal  size,  and  on  section  showed 
normal  colloid  material.  Microscopically,  the  vesicles  appeared  of 
average  size,  filled  with  a  pink-staining  homogenous  colloid  and 
lined  by  a  single  layer  of  cubical  cells.  There  was  no  increase  in 
the  interstitial  tissue  and  but  moderate  congestion  of  the  blood- 
vessels. 

Case  IV.  The  thyroid  was  of  normal  size.  On  section  there  was  a 
slight  decrease  in  the  average  colloid  content.  Microscopically,  the 
acini  were  small  and  for  the  greater  part  lined  with  a  single  layer  of 
epithelium.  The  interstitial  tissue  was  increased  and  contained 
areas  of  hyalinization. 

THE    ADRENALS 

Case  I.  The  capsule  was  of  average  thickness.  The  cells  of  the 
cortex  were  well  preserved  and  normal;  the  medulla  showed 
moderate  congestion. 

Case  II.  The  adrenals  were  equal,  small  and  flat.  They  con- 
tained considerable  fat  in  the  cortex  with  a  broad  inner  zone  and  a 
small  amount  of  white  medulla.  Microscopical  examination  showed 
the  cortex  to  contain  much  lipoid.  At  the  junction  of  cortex  and 
medulla  were  several  large  collections  of  round  cells.  In  the 
reticular  cortical  zone  was  considerable  Iipochrome  pigment. 
The  medulla  was  broad,  taking  the  chromaffin  stain. 

Case  III.  The  adrenals  presented  a  yellow  cortex  and  a  deeply 
stained  pigmented  inner  zone.  Microscopically,  the  glomerular 
zone  was  poor  in  fat,  while  the  glomeruli  of  the  vesicular  zone  were 
evacuolated.  The  whole  gland  was  markedly  congested. 

Case  IV.  The  adrenals,  though  grossly  normal,  microscopically 
showed  thickening  of  the  capsule  and  hyalinization.  In  the  medulla 
the  blood  vessels  were  congested. 

THE    PITUITARY    BODY 

Case  I.  Pars  Anterior.  The  reticular  arrangement  was  not  very 
apparent   as   the   cells  were  large  and  entirely  filled  the  acini. 


1 82  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  blood  sinuses  were  dilated  and  congested  throughout  the 
entire  lobe  except  for  one  area.  The  cells  were  predominantly 
basophilic.  Those  around  the  periphery  were  more  intensely  so, 
but  even  in  the  center  they  were  more  numerous  than  other  types. 
The  cells  were  polygonal  with  well  defined  outlines.  The  cytoplasm 
was  finely  granular.  A  few  contained  one  or  two  vacuoles,  usually 
in  apposition  with  the  nucleus.  The  nuclei  were  generally  large, 
irregularly  spherical,  with  a  well  defined  reticulum  in  whose 
meshes  were  numerous  chromatin  granules.  There  were  usually 
two  or  three  large  irregular  chromatin  masses  mainly  toward  the 
center  of  the  nucleus,  and  many  smaller  ones  principally  at 
the  periphery.  In  one  portion  the  gland  stood  out  in  contrast  to  the 
surrounding  tissue.  While  the  blood  sinuses  were  congested  in  other 
portions,  here  only  a  few  small  capillaries  were  seen.  The  connective 
tissue  stroma  was  swollen,  edematous  and  fragmentary.  The  cells 
were  of  uniform  staining  and  faintly  basophilic.  They  were  swollen 
and  poorly  outlined  with  frayed  and  irregular  margins.  The 
cytoplasm  was  coarsely  granular.  The  nuclei  were  frequently 
pyknotic  or  occasionally  swollen  with  large  clear  spaces  between 
the  chromatin  network.  In  some  instances  there  had  been  a 
rupture  of  the  nucleolar  membrane  and  a  breaking  up  of  its 
substance.  Here  and  there  were  masses  of  protoplasm  without 
nuclei  or  cell  outlines.  This  entire  area  had  the  appearance  of  an 
early  stage  of  coagulation  necrosis  from  deficient  blood  supply. 

Pars  Intermedia.  The  cells  were  mainly  faintly  basophilic  and 
arranged  in  form  of  large  vesicles  filled  with  colloid. 

Pars  Nervosa.  The  neuroglial  cells  appeared  normal.  Some  of 
the  fibers  contained  a  brownish  pigment. 

Case  II.  Pars  Anterior.  The  capsule  was  of  normal  thickness 
and  throughout  the  gland  the  reticular  arrangement  of  connective 
tissue  was  well  marked.  The  blood  sinuses  were  moderately  dilated. 
The  cells  had  no  definite  arrangement  but  formed  irregular  groups. 
Many  were  shrunken  and  in  the  center  of  the  acini,  not  in  apposition 
with  their  walls.  The  central  cells  were  almost  entirely  eosinophilic, 
those  at  the  periphery  were  basophilic.  The  cells  were  of  average 
size  with  well  defined  outlines  and  a  single  deeply  stained  nucleus 
in  the  center.  Scattered  throughout  the  anterior  lobe  were  many  large 
eosinophilic  cells  with  a  granular  cytoplasm.  These,  were  more 
prevalent  around  the  periphery  where  they  frequently  were  the 
only  cells  in  an  individual  acinous  space.  Throughout  the  medial 


MORBID  ANATOMY  183 

portion  of  the  gland  they  were  rarely  seen.  The  vascular  sinuses 
were  dilated.  No  hemorrhages  or  thromboses  were  seen. 

Case  III.  Pars  Anterior.  The  connective  tissue  stroma  appeared 
normal.  The  vessels  were  dilated  and  congested.  The  cells  were 
mainly  basophilic  at  the  periphery,  distinctly  acidophilic  in  the 
center.  Neutrophilic  cells  were  scattered  throughout  the  section 
but  were  in  the  minority.  The  eosinophilic  cells  were  of  average 
size  with  finely  granular  protoplasm  containing  no  vacuoles. 
The  nuclei  were  spherical  and  deeply  stained.  They  contained 
a  chromatin  network  and  granules  but  were  opaque.  The  baso- 
philic cells  were  smaller  than  the  oxyphilic  with  less  clear  and 
more  irregular  margins.  The  cytoplasm  was  more  coarsely  granular 
and  contained  occasional  vacuoles.  The  nuclei  were  large  and 
translucent  with  a  chromatin  network  and  granules.  Two  small 
vessels  were  thrombosed  with  what  appeared  to  be  platelet 
thromboi.  Many  cells  around  these  vessels  were  necrotic.  In  some 
areas  there  was  an  accumulation  of  loosely  granular  cytoplasm  with 
no  nuclei  or  remnants,  in  others  the  nuclei  remained  while  the 
cytoplasm  was  disintegrated.  Some  nuclei  appeared  normal,  others 
were  fragmented  and  degenerated. 

The  pars  intermedia  contained  many  spaces  filled  with  faintly 
basophilic  colloid. 

The  pars  posterior  was  normal. 

Case  IV.  Pars  anterior  showed  marked  congestion.  Micro- 
scopically the  reticular  stroma  was  normal.  The  vascular  spaces 
were  dilated  and  many  contained  a  homogeneous  hyaline  material. 
The  cell  staining  reaction  was  mainly  basophilic,  but  the  central 
cells  were  mostly  neutrophilic  with  a  few  scattered  oxyphilic. 
Most  of  the  basophilic  cells  were  large  and  deeply  stained.  The 
cytoplasm  was  finely  granular  and  rarely  contained  vacuoles. 
The  margins  were  ill-defined.  The  nuclei  were  large,  irregularly 
spherical  or  oval,  occasionally  sausage-shaped  or  triangular.  They 
contained  a  well  marked  chromatin  network  supporting  dense 
granules.  No  thromboses  or  necrotic  areas  were  seen.  The 
juxtoneural   epithelium   and  posterior  lobe  were  missing. 

THE    GONADS 

Case  I.     The  testicles  were  normal. 

Case  II.  Testicles.  The  left  was  soft  and  congested.  The  right, 
also  soft  and  somewhat  smaller  than  the  left,  was  slightly  adherent 


1 84  ACUTE  EPIDEMIC  ENCEPHALITIS 

around  the  epididymis  to  the  parietal  layer  of  the  tunica  vaginalis. 
Microscopically  there  was  no  spermatogenesis  and  practically 
all  of  the  elements  were  absent,  only  the  sustentacular  cells  and 
debris  remaining  in  most  of  the  tubules.  The  basement  membranes 
were  normal.  The  interstitial  cells  contained  considerable  brown 
pigment. 

Case  III.  The  testicles  were  apparently  normal  in  the  gross. 
On  histological  examination  spermatogenesis  appeared  imperfect. 
Many  pyknotic  nuclear  fragments  were  seen,  with  well  preserved 
mitoses  and  apparently  normal  spermatis  and  spermatozoa. 

Case  IV.  The  ovaries  showed  some  old  and  some  more  recent 
corpora  Iutea.  Microscopically,  there  were  a  few  semi-replaced 
corpora  Iutea.  Otherwise  the  entire  ovary  had  been  replaced  with 
fibrous  tissue. 

THE  PANCREAS 

Case  I.  The  pancreas  was  congested  but  otherwise  grossly 
normal.  Microscopically  it  was  normal  except  for  a  few  large 
circular  open  spaces  which  may  have  contained  fat.  Some  had  a 
thin  hyaline  membrane  lining. 

Case  II.     The  pancreas  was  grossly  and  microscopically  normal. 

Case  III.  The  pancreas  was  reddish,  with  marked  congestion  of 
the  blood-vessels.  The  glandular  tissue  had  a  glossy,  digested 
appearance.  On  microscopical  examination  the  acini  were  decreased 
in  size;  the  cytoplasm  of  the  cells  appeared  vacuolated.  Only  a 
few  of  the  islands  of  Langerhans  were  evident,  many  being  replaced 
by  fibrous  tissue.  There  was  increase  of  interstitial  tissue  replacing 
many  glands  and  giving  the  tissue  a  fibrous  appearance.  In  areas 
this  connective  tissue  appeared  necrotic.  The  blood  vessels  were 
sclerotic  and  many  were  obliterated. 

Among  the  clinical  manifestations  of  the  disease  which 
might  be  interpreted  as  endocrine  disturbances  are  profuse 
sweating,  weakness,  low  blood  pressure,  menstrual  disturbances, 
impotence  and  metabolic  disorders  resulting  in  increase  of 
weight.  It  seems  probable  that  further  study  will  show  these 
disturbances  as  dependent  primarily  on  lesions  in  the  nervous 
system,  or  the  direct  effect  of  disease  toxins  on  the  individual 
secretory  organs  causing  altered  functions  without  distinct 
histological  changes. 


MORBID  ANATOMY  185 

SUMMARY  CONCERNING  ENDOCRINE  GLANDS 

With  the  exception  of  the  anterior  lobe  of  the  pituitary, 
there  were  no  definite  pathological  alterations  in  the  glands 
of  internal  secretion. 

In  the  pars  anterior  of  the  pituitary  two  kinds  of  altera- 
tions were  observed — a  predominance  of  basophilic  cells 
and  areas  of  focal  necrosis  and  capillary  thromboses. 

The  normal  histological  variations  in  the  anterior  lobe  of 
the  pituitary  are  marked  and  the  significance  of  the  prepon- 
derance of  the  various  types  of  cells  is  little  understood. 

It  seems  unlikely  that  there  could  be  sufficient  interference 
of  function  in  the  pituitary  body  to  cause  the  lethargy 
of  epidemic  encephalitis.  The  focal  necroses  and  capillary 
thrombi  are  somewhat  similar  to  the  condition  found  in  the 
liver  in  typhoid  fever  and  in  some  cases  of  sepsis.  Here,  as 
in  the  liver,  the  collateral  circulation  is  so  extensive  that  it 
is  difficult  to  believe  that  capillary  thrombi  could  impair 
the  circulation  sufficiently  to  induce  necrosis.  It  seems  more 
probable  that  both  changes  result  from  the  circulating  toxins. 
These  necroses  were  not  prominent  in  the  specimens  studied 
and  it  is  doubtful  if  they  were  sufficient  to  cause  much  alter- 
ation in  the  function  of  the  gland.  So  that,  while  the  altera- 
tions described  in  the  pituitary  are  definite,  there  is  at 
present  no  evidence  that  they  are  important  or  influence  the 
course  or  manifestations  of  the  disease.  To  reach  definite 
conclusions  concerning  the  changes  in  the  internal  secretory 
organs  in  epidemic  encephalitis,  many  more  cases  must  be 
studied. 

The  following  questions  submitted  to  Dr.  Howe  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Tilney:  Were  the  pineal  or  chorioidal  glands  examined  in 
any  of  the  four  cases? 

Dr.  Howe:  No,  only  those  I  mentioned. 

Dr.  Tilney:  Did  the  appearance  of  the  medulla  of  the  adrenal 
suggest  any  marked  departure  from  the  normal? 


1 86  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Howe:  No,  the  medulla  of  the  adrenal  appeared  normal. 
In  one  case  there  was  an  increase  in  the  lymphoid  tissue  between 
the  medulla  and  the  cortex,  but  that  is  normal  and  we  paid  no 
especial  attention  to  it. 

Dr.  Tilney:  In  the  pituitary  body,  did  you  find  any  dispro- 
portion in  the  basophilic  and  the  acidophilic  cells? 

Dr.  Howe:  That,  of  course,  is  a  difficult  point  to  answer.  I 
have  never  seen  two  pituitaries  that  looked  exactly  alike  in  any 
condition,  and  while  as  a  rule  the  oxyphilic  cells  predominate  and 
the  basophilic  cells  are  largely  at  the  outside,  in  these  cases  all 
of  them  I  examined  seemed  to  be  in  a  greater  proportion  than  is 
usually  seen.  I  do  not  know  that  you  could  say  it  was  abnormal, 
but  I  think  you  would  term  it  unusual  in  appearance. 

Dr.  Tilney:  Sometimes  in  inflammatory  conditions  of  the  pit- 
uitary, there  is  an  invasion  of  the  posterior  lobe  by  aciniform 
collections  of  basophilic  cells.  Did  you  find  anything  of  this  kind 
in  the  pars  infundibularis? 

Dr.  Howe:  No;  that  appearance  was  not  found  in  any  of  the 
four  cases. 

Dr.  Tilney:  Concerning  the  residual  lumen,  did  that  contain 
any  increase  or  decrease  of  colloid  substance? 

Dr.  Howe:  All  of  these  cases  were  adults.  I  think  the  youngest 
was  thirty-eight  and  the  oldest  fifty-three.  I  think  one  was  fifty 
and  another  fifty-one,  and  there  was  considerable  colloid,  but  I 
think  not  more  than  is  usual  in  patients  of  this  age. 

Dr.  Tilney:  Do  you  consider  the  thrombosis  of  the  pituitary 
vessels  to  be  specific  of  this  disease? 

Dr.  Howe  :  I  do  not  believe  we  know  enough  about  the  appear- 
ance of  the  pituitary  in  acute  infectious  diseases.  As  a  rule  the 
glands  are  not  saved.  It  is  quite  likely  that  this  does  occur  in  other 
acute  infectious  diseases. 

Dr.  Tilney:  Is  it  your  opinion  in  these  cases  you  have  examined, 
that  the  thyroid,  adrenals,  pituitary,  pancreatic  and  other  endo- 
crinic  elements  play  no  very  important  part  in  the  symptoms  or 
pathological  appearance  of  the  epidemic  encephalitis? 

Dr.  Howe:  I  think  all  that  you  can  say  in  answer  to  that  point 
is  that  if  there  are  alterations  they  are  largely  functional  rather 
than  histological,  and  that  you  cannot  determine  by  a  study  of  this 
kind,  because  the  glands  really  appear  quite  normal  except  for  some 
minor  changes. 


MORBID  ANATOMY  187 

Dr.  Timme:  Did  I  understand  you  to  say  that  the  patient 
showing  pituitary  thrombus  had  lethargy  as  a  symptom? 

Dr.  Howe:  Yes;  the  patient  with  the  thrombi  had  a  period  of 
lethargy  about  three  weeks  before  he  died. 

Dr.  Timme  :  Do  you  know  the  immediate  cause  of  death? 

Dr.  Howe:  In  the  second  case  I  am  sure  it  was  due  to  respira- 
tory paralysis. 

Dr.  Taylor:  You  would  not  say  there  was  anything  specific 
in  any  of  these  lesions,  and  would  call  this  research  therefore 
negative? 

Dr.  Howe:  I  have  never  seen  thrombi  in  the  anterior  lobe  of 
the  pituitary  in  any  other  condition,  and  I  have  never  seen  it 
described  in  the  literature.  But  I  do  not  think  we  know  enough 
about  it  as  yet. 

Dr.  Taylor:  Has  Dr.  Howe  seen  cases  with  great  increase  in 
weight? 

Dr.  Howe:  Yes,  I  have.  I  remember  one  patient  very  distinctly, 
a  young  girl  of  fourteen  who  had  acute  encephalitis  with  a  Parkin- 
sonian residuum,  and  her  greatest  weight  before  was  107  pounds.  In 
six  months  after  this  period  she  gained  so  as  to  weigh  149.  I 
have  seen  one  or  two  others  of  marked  increase  in  weight.  But  I 
have  not  been  able  to  study  that  patient  thoroughly  yet,  and  do 
not  know  whether  she  presents  any  other  pituitary  signs.  I  know 
that  menstruation  came  on  during  her  first  illness  and  has  pro- 
ceeded regularly  ever  since.  The  only  cases  of  impotence  that 
I  have  seen  have  been  in  patients  having  the  paralysis  agitans 
type.  I  have  seen  that  occur  several  times. 

Dr.  Timme:  Have  you  seen  any  cases  in  which  there  has  been 
marked  pigmentation  to  the  extent  of  bronzing  the  entire  body? 

Dr.  Howe:  No,  I  have  not. 

Lesions  Outside  of  the  Central  Nervous  System 
(William  Boyd).  It  would  appear  that  encephalitis 
Iethargica  must  be  regarded  as  a  general  infection  with 
special  localization  in  the  central  nervous  system.  It  is 
possible,  however,  that  in  many  cases  such  localization  never 
takes  place,  and  that  the  patient  suffers  merely  from  some 
mild  febrile  disturbance  the  nature  of  which  is  never  recog- 
nized. 


188  ACUTE  EPIDEMIC  ENCEPHALITIS 

Changes  in  the  Serous  Membranes.  Petechial  hemor- 
rhages in  the  serous  membranes  identical  with  those  found  in 
conditions  of  septicemia  occasionally  occur.  In  three  cases 
in  a  series  of  sixteen  autopsies  widespread  petechial  hemor- 
rhages were  observed  scattered  over  the  epicardium,  the 
pleura  on  both  sides,  the  peritoneum  and  both  surfaces  of  the 
diaphragm.  The  condition  was  so  striking  as  to  suggest  at 
once  the  possibility  of  a  septicemia,  but  the  brain  findings 
were  those  characteristic  of  encephalitis  Iethargica.  In  two 
other  cases  there  were  small  hemorrhages  under  the  endo- 
cardium. 

Microscopic  Changes  in  the  Kidneys.  The  kidney  was 
examined  in  eight  cases  and  in  every  instance  showed 
changes  which  appeared  to  be  distinctly  pathological. 
The  kidney  lesions  were  of  two  main  types,  vascular  and 
tubular. 

The  vascular  changes  consisted  in  intense  congestion  of  the 
capillaries.  This  was  most  marked  in  the  straight  vessels  of 
the  medulla,  many  of  which  were  so  distended  as  to  produce 
narrowing  of  the  lumen  of  the  collecting  tubes.  In  places 
hemorrhage  had  occurred  from  these  distended  vessels  into 
the  tubules.  Occasionally  the  vascularity  in  the  medulla  was 
so  great  as  to  suggest  the  edge  of  an  infarct.  Both  the 
glomeruli  and  the  intertubular  plexus  showed  a  moderate 
degree  of  congestion,  and  a  few  red  blood  cells  could  be  seen 
in  the  capsular  space  of  some  of  the  glomeruli.  The  above 
description  is  that  of  a  severe  example  of  the  condition,  but 
minor  degrees  of  intensity  were  constantly  present.  The 
tubular  lesions  were  degenerative  in  character,  and  resembled 
those  of  the  nephrosis  described  by  Volhard  and  Fahr,  or  the 
tubular  nephritis  produced  by  such  an  irritant  as  corrosive 
sublimate. 

The  cells  to  suffer  most  were  those  of  the  convoluted 
tubules  and  the  ascending  limb  of  Henle.  In  every  case  there 
was  a  marked  degree  of  cloudy  swelling,  and  in  a  few 
instances  the  nuclei  had  disappeared  and  the  cells  were 
completely  disintegrated.  The  contrast  between  the  con- 


MORBID  ANATOMY  189 

voluted  and  the  collecting  tubules  in  the  more  marked  cases 
was  striking  in  the  extreme. 

It  must  not  be  thought,  however,  that  the  collecting 
tubules  escaped  entirely  in  every  instance.  In  several  cases 
the  lining  cells  were  crowded  with  yellow  granules.  As  these 
were  most  abundant  in  areas  where  hemorrhage  had  oc- 
curred, it  is  probable  that  they  were  of  the  nature  of  blood 
pigment.  In  one  case  the  cells  of  the  collecting  tubules  con- 
tained granules  which  gave  a  fat  reaction  with  Scarlet  R  in 
frozen  sections.  The  convoluted  tubules  in  this  case,  although 
profoundly  degenerated,  gave  no  fat  reaction. 

An  additional  lesion  was  observed  in  one  of  the  cases  with 
widespread  petechial  hemorrhages  in  the  serous  membranes. 
Most  marked  in  the  boundary  zone  between  the  cortex  and 
the  medulla  although  to  a  lesser  extent  elsewhere  throughout 
the  cortex,  there  were  found  collections  of  small  round  cells 
with  a  few  polymorphonuclear  cells.  These  strongly  sug- 
gested a  focal  infection,  and  the  appearance  was  not  unlike 
that  of  a  suppurative  nephritis. 

Appearance  of  Homogeneous  Hyaline  Bodies  in  the  Central 
Nervous  System.  A  change  worthy  of  note  was  the  presence 
of  numerous  spherical,  homogeneous  hyaline  bodies,  resem- 
bling the  corpora  amylacea  found  in  the  prostate  and  other 
organs.  These  bodies  were  found  in  severe  cases,  in  the  young 
as  well  as  the  elderly.  As  a  rule  they  were  of  uniform  size, 
but  occasionally  showed  variations  in  diameter.  The  center 
was  darker  than  the  periphery,  but  there  was  no  definite 
nucleus.  Concentric  striations  could  be  made  out  in  many 
instances.  In  one  case  they  were  present  in  the  cerebrum, 
basal  ganglia,  midbrain,  pons,  medulla  and  cord,  but  not  in 
the  cerebellum.  Although  present  in  both  giay  and  white 
matter  throughout  the  brain  and  cord,  they  were  most 
numerous  at  the  surface,  around  the  aqueduct  of  Sylvius, 
and  under  the  floor  of  the  fourth  ventricle. 

The  bodies  stained  blue  with  thionin,  pale  blue  with 
hematoxylin,  blue-black  with  iodine,  but  not  at  all  with  van 
Gieson.  They  are  probably  products  of  degeneration,  similar 


iqo  ACUTE  EPIDEMIC  ENCEPHALITIS 

to  the  colloid  bodies  found  in  old  age.  They  appear  to  be  due 
to  neuroglial  degeneration.  They  are  certainly  not  derived 
from  ganglion  cells,  for  they  are  as  numerous  in  the  white  as 
in  the  gray  matter. 

Lesions  in  the  Brain  Produced  by  Lead  and  other 
Poisons  Contrasted  with*  those  of  Epidemic  Encepha- 
litis (George  B.  Hassin).  Non-suppurative  inflammations 
of  the  brain  generally  termed  encephalitis  may  be  caused  by 
infections  or  intoxications.  The  infectious  group  is  mainly 
represented  by  general  paralysis  and  epidemic  encephalitis; 
the  toxic  group  by  intoxications  such  as  lead  or  arsenic.  In 
both  these  large  groups  of  non-suppurative  inflammation  of 
the  brain  there  are  to  be  found  parenchymatous  (or  better, 
ectodermic)  and  interstitial  (or  mesodermic)  changes. 

Ectodermal  Changes  Contrasted.  The  ectodermic  changes, 
that  is  to  say,  those  of  the  neuroglia  and  ganglion  cells,  do 
not  exhibit  any  specific  pathologic  features,  being  practically 
alike  in  the  epidemic  and  the  lead  varieties  of  encephalitis. 
In  both  forms  there  is  present  an  excessive  number  of  glia 
nuclei,  which  may  be  somewhat  increased  in  size  and  possess 
a  visible  rim  of  cytoplasm.  However,  in  both  large  proto- 
plasmic glia  cells,  myeloclasts,  myelophages  as  well  as 
various  types  of  gitter  cells  are  absent.  As  to  the  changes  in 
ganglion  cells  and  nerve  fibers,  the  former  are  represented  by 
chromatolysis,  neuronophagia,  satellitosis,  and  accumula- 
tion of  fat-like  substances.  In  short,  the  parenchymatous 
changes  are  degenerative  in  character. 

Mesodermic  Changes  Contrasted.  Of  much  greater  signi- 
ficance are  the  mesodermic^changes  to  be  found  in  the  vessels 
and  the  pia-arachnoid.  In  epidemic  encephalitis,  the  vessels 
are  much  infiltrated,  chiefly  with  lymphocytes  and  plasma 
cells,  the  infiltration  frequently  transgressing  the  perivascu- 
lar spaces  and  invading  the  parenchyma  itself.  The  latter 
is  frequently  covered  with  dense  foci  of  hematogenous 
elements,  mixed  with  many  glia  cells,  totally  obscuring  the 
parenchyma.  Such  dense  infiltrations  do  not  occur  in  lead 


MORBID  ANATOMY  191 

encephalitis.  Here  the  vascular  changes  are  mainly  repre- 
sented by  proliferative  phenomena.  Thus,  there^jmay,  be 
hypertrophy  of  the  endothelial  cells  of  the  capillaries  with  an 
abundance  of  intensely  stained  protoplasm;  there  may  be 
proliferated  and  hypertrophied  fibroblasts;  there  may  be  an 
abundance  of  new-formed  capillaries  in  the  shape  of  buddings 
or  off-shoots;  the  vessel  walls  may  be  thickened,  etc.  In 
short,  all  the  various  stages  or  phases  of  proliferation  or 
new  formation  of  capillaries  may  be  encountered  in  toxic 
encephalitis,  but  not  in  the  epidemic  variety. 

The  vascular  changes  in  the  epidemic  form  are  confined 
principally,  though  not  exclusively,  to  the  midbrain,  while 
in  the  toxic  variety  the  changes  above  described  are  almost 
universal.  They  affect  every  portion  of  the  cerebrum  and 
cerebellum  including  the  pia-arachnoid  and  its  spaces. 

The  latter  structures  show  particularly  noteworthy 
changes.  In  lethargic  encephalitis  they  consist  of  mild 
infiltration  with  lymphocytes  and  plasma  cells  while  in  lead 
encephalitis,  especially  in  early  stages,  the  cell  infiltration 
is  much  more  marked,  in  fact  may  be  enormous,  always 
combined  with  great  wealth  of  vessels,  both  pre-  and  new- 
formed.  The  pial  infiltration  elements,  in  lead  encephalitis 
are  more  numerous,  the  mesothelial  cells,  polyblasts  and 
fibroblasts  being  especially  conspicuous.  There  are  also 
many  other  elements  mostly  ill-defined  and  frequently 
packed  with  pigment  granules.  Such  conditions  ultimately 
lead  to  a  general  hyperplastic  state  of  the  pia-arachnoid, 
especially  on  the  base  of  the  brain,  in  the  region  of  the  optic 
chiasm  and  around  the  cerebellum. 

The  prevalence  of  proliferative  mesodermal  changes 
fully  justifies  the  name  "productive"  encephalitis  which 
Bonfiglio  proposed  for  such  conditions,  while  the  infectious 
variety  should  be  termed  "infiltrative"  encephalitis.  How- 
ever marked  and  important  the  vascular  changes  in  the 
cerebral  substance,  those  of  the  pia-arachnoid  and  the  sub- 
arachnoid space*are  of  greater  significance.  Special  attention 
should  be  paid  to  these  structures  in  pathologic  studies  of 


192  ACUTE  EPIDEMIC  ENCEPHALITIS 

typical    and    atypical    brain    lesions,  for  they  may  reveal 
changes  even  when  the  brain  tissue  proper  appears  normal. 

The  following  questions  submitted  to  Dr.  Hassin  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 

Dr.  Taylor:  Would  you  consider  it  possible  that  changes 
you  describe  as  distinguishing  the  toxic  encephalitis  from  the 
epidemic  might  be  due  to  the  time  element?  Would  it  be  possible 
that  if  the  encephalitic  process  could  be  studied,  for  example, 
years  after,  we  might  find  proliferation  of  vessels?  Do  you  think, 
in  other  words,  there  is  a  specific  difference? 

Dr.  Hassin:  It  is  absolutely  specific  in  the  cases  I  studied. 
I  had  three;  two  were  chronic  cases  of  ten  months  duration,  and 
these  pictures  are  taken  from  an  acute  case  of  five  weeks  duration. 

Dr.  Tilney:  In  your  Case  3  you  state  that  only  the  pro- 
ductive changes  occur  in  the  more  chronic  cases  of  lead  encephalitis. 
Would  you  consider  it  necessary  to  take  into  account  the  possi- 
bility of  the  influence  of  time  here? 

Dr.  Hassin:  In  pial  acute  cases  there  are  only  proliferic  changes. 
The  "productive"  type  of  encephalitis  is  typical  for  brain  lesions 
caused  by  lead  poisoning. 

Dr.  Taylor:  Were  your  lead  poisoning  sections  taken  from 
animals,  experimental  matter  or  fatal  cases? 

Dr.  Hassin:  From  fatal  human  cases. 

CONCLUSIONS  OF  THE  COMMISSION 

Material.  It  is  the  opinion  of  the  Commission  that  while 
much  knowledge  has  been  gained  from  the  pathological  ma- 
terial already  obtained,  the  number  of  cases  subjected  to 
autopsy  up  to  this  time  is  nevertheless  too  small  to  permit  of 
any  final  deductions  concerning  the  pathology  of  epidemic 
encephalitis.  Furthermore,  the  Commission  feels  that  the 
pathological  material  thus  far  investigated  has  not  been 
studied  with  sufficient  thoroughness  to  permit  of  more  than 
an  outline  or  sketch  of  the  entire  pathological  process  of  the 
disease  at  the  present  juncture.  This  is  especially  true  of  the 


MORBID  ANATOMY  193 

cerebral  cortex  and  for  that  matter  of  the  brain  stem  and 
spinal  cord.  Intensive  studies  by  means  of  appropriate  differ- 
ential stains  upon  specimens  treated  in  serial  sections  will 
afford  the  most  reliable  basis  from  which  to  draw  definitive 
conclusions. 

The  investigations  of  lesions  in  parts  other  than  the  ner- 
vous system  and  particularly  in  the  endocrine  organs  like- 
wise comprise  studies  upon  cases  much  too  limited  in  number 
to  warrant  ultimate  deductions. 

The  contrasts  between  the  histological  changes  due  to 
epidemic  encephalitis  and  histological  changes  caused  by 
other  inflammatory  toxogenic  factors,  although  appearing 
in  some  instances  to  be  well  defined,  are  not  yet  sufficiently 
established  to  warrant  a  statement  that  there  is  a  complete 
specificity  in  the  pathological  process  of  epidemic  encephalitis. 

The  total  number  of  cases  up  to  December,  1920,  in  which 
there  have  been  necropsy  observations  is  113.  For  purposes 
of  histological  comparison  and  topographical  orientation, 
not  more  than  50  of  these  cases  are  available.  No  single  case 
has  been  examined  with  the  completeness  of  technical  detail 
or  anatomical  comprehensiveness  entirely  satisfactory  from 
the  pathological  standpoint. 

The  results  of  experimental  pathology,  although  of  much 
interest  and  very  Suggestive,  are  yet  too  meagre  to  Contribute 
measurably  to  the  conception  of  the  morbid  process  of  the 
disease. 

Gross  Pathology.  Upon  inspection  the  dura  mater  has 
shown  no  constant  lesion.  The  pia-arachnoid  is  often  edema- 
tous but  quite  as  often  shows  no  pathological  changes. 
The  surface  of  the  brain  is  congested,  sometimes  intensely 
so.  Free  blood  may  be  seen  in  the  sulci  but  massive  pial 
hemorrhage  is  rare.  The  convolutions  may  be  somewhat 
flattened.  The  lesions  are  most  intense  in  the  midbrain, 
pons  and  medulla,  least  in  the  cerebellum.  The  ventricles 
are  usually  normal  in  size  and  appearance  and  contain 
cerebrospinal  fluid  of  normal  appearance.  The  ependyma, 

13 


194  ACUTE  EPIDEMIC  ENCEPHALITIS 

usually  smooth  and  glistening,  is  occasionally  slightly  rough- 
ened. The  meninges  and  surface  of  the  spinal  cord  in  many 
cases  resemble  the  cerebral  meninges  and  surfaces. 

Microscopic  Changes  in  the  Central  Nervous  Sys- 
tem. Histologically  the  essential  changes  in  the  brain  and 
spinal  cord  are: 

a.  Cellular  infiltration  chiefly  affecting  the  small  veins  and, 
to  a  less  extent,  the  larger  veins,  arteries  and  capillaries. 
The  infiltrating  cells  are  small  and  large  mononuclear 
lymphocytes  and  plasma  cells.  The  infiltration  is  largely 
confined  to  the  Virchow-Robin  and  perivascular  spaces.  It 
has  its  greatest  intensity  in  the  gray  matter  of  the  basal 
ganglia,  midbrain,  pons,  medulla  and  spinal  cord.  The  white 
matter  is  not  entirely  immune. 

b.  Hemorrhage  which  is  usually  microscopic  and  confined 
to  the  perivascular  spaces  of  His  is  also  a  prominent  feature. 
There  is  an  almost  complete  absence  of  thrombosis,  and  if 
hemorrhage  occurs  into  the  brain  substance  it  is  accompanied 
by  a  reaction  of  the  surrounding  glia.  In  some  cases  spherical, 
homogeneous,  hyaline  bodies  resembling  corpora  amylacea 
appear  in  the  affected  areas  of  the  central  nervous  system. 

c.  Cellular  Changes.  The  nerve  cells  and  their  fibers  show 
relatively  little  evidence  of  degenerative  change  in  proportion 
to  the  severity  of  the  pathological  lesion.  In  areas  of  the 
most  intense  changes  the  nerve  cells  often  manifest  some 
degree  of  cloudy  swelling,  chromatolysis,  disintegration  of 
the  neurofibrils,  satellitosis  and  neuronophagia.  The  neurog- 
lial cells  show  marked  proliferation  in  areas  characterized 
by  pronounced  changes  in  the  nerve  cells  or  in  the  more 
intensely  hemorrhagic  foci. 

Microscopic  Change  in  the  Meninges.  The  pia- 
arachnoid  may  be  normal.  Usually  the  pial  vessels  are  engor- 
ged. The  pial  layers  may  be  separated  and  the  pial  reticulum 
distended  with  numerous  red  corpuscles  and  mononuclear 
cells  in  the  interstices.  In  the  sulci  intrapial  extravasations 
frequently  occur. 


MORBID  ANATOMY  195 

Microscopic  Changes  in  the  Nerve  Roots  and  Dorsal 
Root  Ganglia.  In  some  cases  the  cranial  nerves  have  been 
found  to  be  the  seat  of  a  perivascular  lymphocytic  infiltra- 
tion and  an  interstitial  infiltration  of  the  nerve  fibers  by 
lymphocytes.  Evidence  is  still  lacking  concerning  the  involve- 
ment of  the  spinal  nerves,  nerve  roots  and  dorsal  root  ganglia. 

Fundamental  Microscopic  Changes  in  Acute  Cases. 
The  essential  histological  alteration  in  all  acute  cases  almost 
universally  appears  to  involve  primarily  the  mesodermal 
structures  with  infiltration  of  the  walls  of  the  smaller  vessels 
and  the  perivascular  lymph  spaces  with  lymphocytes, 
plasma  and  large  mononuclear  cells. 

Microscopic  Changes  in  Cases  of  Long  Duration. 
Chronic  cases  usually  differ  histologically  from  acute  cases. 
After  a  duration  of  several  months  the  vessel  walls  thicken 
and  frequently  contain  calcareous  plaques.  The  Iumina  are 
frequently  closed  by  fibrous  or  fibrinous  occlusions.  Peri- 
vascular infiltration  is  still  present  and  neuroglial  prolifera- 
tion is  more  pronounced. 

Microscopic  Changes  in  the  Endocrine  Organs.  The 
only  alteration  which  may  be  of  pathological  moment  in  the 
endocrine  system  is  the  occurrence  of  focal  necrosis,  capillary 
thrombosis  and  a  predominance  of  basophilic  cells  in  the  pars 
anterior  of  the  pituitary  body.  This  was  observed  in  two  cases 
only.  The  thyroid,  adrenals,  pancreas  and  gonads  (testes  and 
ovaries)  were  found  normal  in  all  the  cases  examined.  The 
Commission  is  not  disposed  to  attach  much  importance  to  the 
pathological  chahges  in  the  pituitary  body  and  feels  that 
altogether  too  few  cases  have  yet  been  examined  with  re- 
ference to  the  histological  state  of  the  endocrine  organs  to 
make  any  statement  regarding  the  pathology  of  these  organs 
in  epidemic  encephalitis  tenable.  The  most  that  may  be 
vouchsafed  is  that  from  limited  findings  the  evidence  of 
pathological  alteration  seems  almost  negligible. 


196  ACUTE  EPIDEMIC  ENCEPHALITIS 

Reports  on  the  condition  of  the  pineal  and  chorioidal 
glands  are  thus  far  not  forthcoming. 

Lesions  Outside  of  the  Nervous  System,  a.  The  serous 
membranes  have  been  found  to  be  affected  by  changes 
resembling  the  conditions  of  septicemia.  Petechial  hemor- 
rhages have  been  observed  in  the  epicardium,  pleura,  peri- 
toneum and  both  surfaces  of  the  diaphragm.  In  several  cases 
small    hemorrhages    were    found    under    the    endocardium. 

b.  The  kidney  was  also  found  to  present  pathological 
changes  which  were  vascular  and  tubular.  The  vascular 
changes  consisted  of  intense  capillary  congestion  with 
scattered  hemorrhages.  The  tubular  lesions  were  degenera- 
tive in  character,  resembling  those  of  nephrosis  described  by 
Volhard  and  Fahr,  i.  e.,  the  tubular  nephritis  produced 
by  such  an  irritant  as  corrosive  sublimate. 

Lesions  of  Epidemic  Encephalitis  Contrasted  with 
Those  Produced  by  Lead  and  Other  Poisons.  It  is  note- 
worthy that  while  ectodermal  changes  are  very  similar  in 
lead  encephalitis  and  epidemic,  the  mesodermal  changes  in 
these  conditions  are  quite  different.  In  epidemic  encephalitis 
the  vessels  are  much  infiltrated,  this  infiltration  frequently 
invading  the  perivascular  spaces  and  the  parenchyma.  This 
degree  infiltration  does  not  occur  in  lead  encephalitis,  which 
shows  mainly  proliferation  of  the  endothelial  cells  of  the 
capillaries  and  thickening  of  the  vessel  walls.  The  vascular 
changes  in  epidemic  encephalitis  are  more  closely  confined  to 
the  midbrain;  whereas  in  lead  encephalitis  the  changes  are 
almost  universal  throughout  the  brain. 


Chapter  VII 

BACTERIOLOGY    AND    ANIMAL    EXPERIMENTA- 
TION; FURTHER  STUDIES  IN  PATHOGENE- 
SIS, IMMUNOLOGY  AND  PHYSIOLOGI- 
CAL  FUNCTIONING 

THE  material  presented  in  this  chapter  consists  of  reports 
of  various  contributors,  namely,  additional  reports  by 
Drs.  Leo  Loewe  and  Israel  Strauss  of  the  Laboratory  of 
Mt.  Sinai  Hospital,  New  York  City;  of  further  remarks 
by  Dr.  William  Thalhimer  of  Milwaukee;  of  the  report  of 
immunological  distinctions  of  encephalitis  and  poliomyelitis 
by  Dr.  Harold  L.  Amoss  of  the  Rockefeller  Institute;  of 
immunological  studies  by  Drs.  Marcus  Neustaedter,  John  H. 
Larkin,  and  E.  J.  Banzhaf  of  New  York;  and  finally  of  certain 
physiological  interpretations  of  the  function  of  the  nervous 
system  in  respect  to  those  diseases  by  Professor  Frank  H.  Pike 
of  the  College  of  Physicians  and  Surgeons,  New  York  City. 

Cultivation  of  the  Virus  (Leo  Loewe).  Early  in  the 
work  it  became  evident  to  Loewe  and  Strauss  that  the  virus 
of  the  disease  resides  in  the  nasopharynx.  The  filtrate  of  a 
profuse  nasal  discharge  from  a  patient  was  injected  subdur- 
ally  into  a  monkey.  Paralysis  of  both  hind  legs  followed  in 
seven  days  and  cleared  up  in  two  weeks.  Lumbar  puncture 
revealed  increase  in  cells, — up  to  thirty-five  lymphocytes 
per  cubic  millimeter.  This  monkey  was  subsequently  shown 
to  have  acquired  an  immunity.  Further  investigations  were 
carried  out  along  this  line  with  human  nasopharyngeal 
washings.  It  was  also  found  experimentally  that  the  virus 
is  excreted  through  the  nasopharynx.  The  inoculation  intra- 
cranially  into  rabbits  of  filtrates  of  nasopharyngeal  washings 
has  become  a  method  of  diagnosis.  As  noted  on  the  chart  it 

197 


198  ACUTE  EPIDEMIC  ENCEPHALITIS 

is  a  method  which  has  given  a  positive  result  in  16  out  of  21 
cases,  or  77  per  cent.  There  are  cases  of  encephalitis  which 
do  not  present  the  classical  symptoms  of  the  disease,  and  it  is 
in  such  cases  that  rabbit  inoculation  has  been  especially 
valuable.  The  test  was  positive  in  one  case  of  relapse.  Results 
seem  to  point  rather  conclusively  to  the  nasopharynx  as  the 
portal  of  entry  of  the  infection. 

Inoculation  of  spinal  fluids  into  monkeys  and  rabbits  has 
demonstrated  that  the  virus  is  present  in  the  fluid  especially 
in  those  cases  which  show  an  increase  in  cells.  The  inoculation 
of  spinal  fluid  into  rabbits  for  diagnosis  in  conjunction  with 
the  nasal  washing  method  has  been  employed.  Sixty  rabbits 
were  so  injected  with  spinal  fluids  from  28  cases.  Lesions  were 
produced  in  23  animals,  thus  establishing  the  diagnosis  in 
1 7  of  the  28  cases,  or  60  per  cent. 

To  control  this  work  nine  nasal  washings  and  twelve  spinal 
fluids  from  various  neurological,  medical  and  surgical  cases, 
preferably  surgical,  to  rule  out  the  possibility  of  contact 
infection,  were  inoculated.  The  results  were  entirely  negative. 
Two  of  the  control  spinal  fluids  were  from  poliomyelitis  cases. 
Three  of  the  nasal  washings  were  from  influenza  cases. 

That  the  disease  is  at  times  a  general  infection  is  attested 
to  by  our  positive  inoculations  with  blood. 

In  establishing  a  diagnosis  of  encephalitis  in  animals  we 
have  been  guided  by  symptomatology,  the  pathological 
picture  and  cultural  studies.  The  histological  and  cultural 
studies  have  been  of  most  value.  The  lesions  in  experimental 
animals  are  similar  both  in  degree  and  localization  to  the 
well-recognized  lesions  in  the  human  cases.  Throughout  our 
extensive  animal  experimentation  we  have  never  met  the 
spontaneous  production  of  the  characteristic  lesions.  We 
have  resorted  to  the  intravenous  inoculation  of  both  virus 
and  culture  in  several  instances  in  order  to  demonstrate  a 
selective  affinity  of  the  virus  and  culture  for  the  central 
nervous  system.  One  experiment  is  particularly  striking. 
In  attempting  to  obtain  a  specific  serumtin  the  sheep  a 
number  of  intravenous  injections  with  killed  cultures  were 


ANIMAL  EXPERIMENTATION 


199 


given  and  then  a  fairly  large  dose  of  a  virulent  culture  was 
injected.  After  a  period  of  four  weeks  the  sheep  developed 
symptoms  of  a  meningoencephalitis,  to  which  it  succumbed 
in  eight  days.  Spinal  puncture  showed  eighty-five  Iympho- 


*****       ^: 


Fig.  20.     Human  brain.  Focal  infiltrations  with  mononuclear  cells  in  the  puta- 

men  (lenticular  nucleus). 

cytes  per  cubic  millimeter.  An  intense  encephalitis  was 
present.  The  other  organs  showed  no  abnormalities.  The 
classical  picture  was  produced  in  a  series  of  rabbits  by  means 
of  intracranial  and  intravenous  inoculation  with  saline 
emulsions  and  Berkefeld  filtrates  of  this  brain.  The  organism 


200 


ACUTE  EPIDEMIC  ENCEPHALITIS 


was  recovered  from  the  original  sheep  brain  and  from  several 
of  the  rabbits  of  the  series.  These  experiments  are  being 
prosecuted  for  subsequent  publication. 

The  materials,  after  preliminary  cultivation  on  the  usual 


Fig.  21.     Human  brain.  Mononuclear  cell  infiltration  in  the  Virchow-Robin 
and  perivascular  spaces  of  vessel  in  the  tegmentum  of  the  midbrain. 

media  to  rule  out  contaminants,  were  put  in  the  tissue- 
ascitis  fluid  medium,  perfected  by  Noguchi.  Anaerobic  con- 
ditions were  assured  by  the  use  of  kidney  tissue,  by  sealing 
with  petrolatum,  and  later  by  the  addition  of  glucose.  It 
should  be  emphasized  that  the  secret  of  success  in  this 


ANIMAL  EXPERIMENTATION 


201 


method  is  the  use  of  a  suitable  ascitic  fluid.  The  organism  is 
a  minute  filtrable  Gram-positive  coccus  appearing  in  diplo- 
forms,  chains  and  clumps.  It  stains  best  by  prolonged  con- 
tract with  methylene  blue,  Giemsa  or  polychrome  methylene 


Fig.  22.  Monkey  brain.  Edema,  necrosis  and  adventitial  infiltration  of  ves- 
sel in  cortex.  Animal  injected  intracerebrally  with  emulsion  of  brain  of  monkey 
successfully  inoculated  with  infected  human  brain  (Loewe  and  Strauss). 

blue.  Morphologically  and  culturally,  the  organism  found 
by  us  resembles  that  found  by  Flexner  and  Noguchi  in 
poliomyelitis. 

The  organism  has  been  isolated  in  pure  culture  from  the 
following  materials. 


202 


ACUTE  EPIDEMIC  ENCEPHALITIS 


i .  Human  nasopharyngeal  mucous  membrane  removed  at 
necropsy.  The  organism  has  been  recovered  in  pure*culture 
from  Berkefeld  filtrate  of  nasopharyngeal  mucous  membranes 
from  8  fatal  cases  of  epidemic  encephalitis.  Out  of  eleven 


Fig.  23.     Monkey  brain.  Cortex  showing  perivascular  infiltration  of  mono- 
nuclear cells.  Animal  same  as  that  pictured  in  Fig.  22  (Loewe  and  Strauss). 


attempts,  eight  or,  73  per  cent  have  been  successful.  The 
organisms  have  been  carried  as  far  as  sixteen  generations 
in  artifical  cultures  without  animal  passage.  The  later  strains 
proved  pathogenic  for  animals.  Control  cultures  of  filtrates 


ANIMAL  EXPERIMENTATION  203 

of  nasopharyngeal   mucous   membranes   of  seven   patients 
dying  of  other  conditions  have  all  been  sterile. 

2 .  Berkefeld  filtrates  of  human  nasopharyngeal  washings  of 
23  cases,  typical  and  atypical,  were  cultivated  with  positive 


<fi 


fit' 


*y\ 


Fig.  24.     Monkey  brain.  Cortex  showing  perivascular  infiltration  with  mono- 
nuclear cells.  Animal  same  as  that  pictured  in  Fig.  22  (Loewe  and  Strauss). 

findings  in  1 5  cases,  or  66  per  cent.  Many  of  these  strains  were 
subcultivated  successfully  and  carried  along  for  several 
generations.  The  later  generations  of  these  cultures  again 
were  pathogenic  for  animals.  Control  studies  were  negative 
in  9  cases— mastoiditis,  sinusitis,  cholelithiasis,  etc. 


204 


ACUTE  EPIDEMIC  ENCEPHALITIS 


3.  Filtrates  of  rabbit  nasopharyngeal  mucous  membrane 
yielded  the  organism  in  3  cases.  The  rabbits  were  injected 
with  both  filtrate  and  culture.  The  organism  was  recovered 
also  from  the  brains  of  animals  injected  with  filtrate  of  these 


Fig.  25.  Monkey  brain.  Mononuclear  cell  infiltration  in  Virchow-Robin 
space  (adventitia) .  Pons.  Animal  inoculated  with  emulsion  of  brain  from  a 
human  case  (Loewe  and  Strauss). 

nasopharyngeal  mucous  membranes  and  also  from  the 
brains  of  animals  injected  with  the  organism  derived  from 
these  rabbit  mucous  membranes.  Cultures  of  filtrates  from 
seven  normal  rabbit  mucous  membranes  were  negative. 


ANIMAL  EXPERIMENTATION 


205 


4.  Cerebrospinal  fluids  have  been  cultured  in  28  cases  with 
fourteen  positive  results.  The  strains  were  carried  as  far  as 
the  eighth  generation  in  order  to  prove  their  pathogenicity. 
Control  spinal  fluid  cultures  were  negative  in  12  cases.  Two 


Fig.  26.  Rabbit  brain.  Mononuclear  cell  infiltration  in  the  meninges  of 
the  cerebrum.  Animal  injected  with  Berkefeld  filtrate  of  nasopharyngeal 
mucous  membrane  from  a  fatal  human  case  (Loewe  and  Strauss). 

of  these  control  spinal  fluids  were  from  poliomyelitic  animal 
inoculations  and  cultures  were  made  in  most  cases  imme- 
diately after  withdrawal  of  the  fluid. 

Rabbit  Brains.     A  total  of  one  hundred  and  twenty-four 


206  ACUTE  EPIDEMIC  ENCEPHALITIS 

rabbit  brains  were  cultivated,  using  Berkefeld  filtrates  of 
brain,  blocks  of  brain  and  emulsions  of  brain.  There  were 
seventy-nine  positives,  or  64  per  cent.  There  was  one  series 
of  seven   animal   transmissions   initiated   by   a    Berkefeld 


Fig.  27.  Rabbit  brain.  Perivascular  infiltration  (principally  mononuclear 
cells)  of  vessels  in  the  midbrain.  Third  transmission  in  rabbit  of  virus  originally 
derived  from  human  nasopharyngeal  mucous  membrane  (Loewe  and  Strauss) . 

filtrate  of  a  human  nasopharyngeal  mucous  membrane.  The 
organism  was  recovered  following  each  transmission.  One 
of  the  organisms  recovered  from  this  series  was  injected 
into  animals  in  the  fourth,  fifth,  sixth,  seventh,  and  eighth 


ANIMAL  EXPERIMENTATION 


207 


generations,  and  was  recultivated  from  50  per  cent  of  the 
brains  so  inoculated.  In  a  series  of  transmissions  initiated  by 
spinal  fluid  from  a  case  of  encephalitis,  the  organism  was 
recovered  from  the  brain  in  each  of  the  transmissions,  the 


Fig.  28.  Rabbit  brain.  Area  of  focal  necrosis  in  proximity  to  vessels 
showing  the  perivascular  infiltration.  Midbrain.  Fourth  transmission  in  rabbit 
of  virus  derived  from  human  nasopharyngeal  mucous  membrane  (Loewe  and 
Strauss). 

positive  results  making  a  total  of  five  of  the  eight  brains 
cultivated. 

Monkey  Brains.  Cultures  were  made  of  six  monkey  brains 
injected   with   virus  of  various   kinds   (filtrates  of  human 


208 


ACUTE  EPIDEMIC  ENCEPHALITIS 


nasopharyngeal  mucous  membrane,  and  of  infected  nervous 
tissue  from  rabbit,  monkey  and  human)  and  five  positive 
results  were  obtained. 


•     !u'  t9'  -,  am*  Area  °f  f°CaI  infiItration  with  mononuclear  cells 

m  the  basilar  ganglia.  Animal  injected  with  Berkefeld  filtrate  of  brain  of 
monkey  successfully  inoculated  with  virus  derived  from  human  nasopharyn- 
geal mucous  membrane,  and  which  had  been  transmitted  through  four  genera- 
tions in  rabbits  (Loewe  and  Strauss). 

Human  Brains.  The  organisms  have  been  obtained  in 
pure  culture  from  eight  brains.  Their  results  have  shown  that 
the  organism  is  more  readily  recovered  from  the  brains  of 
those  cases  that  run  a  rapid  course.  They  have  demonstrated 


ANIMAL  EXPERIMENTATION 


209 


that  there  may  be  a  general  invasion  of  the  blood-stream  in 
both  humans  and  animals. 

As   in   the   case   of  the   virus,    monkeys   are   apparently 
refractory  to  cultures  of  the  organisms.  The  cultures  have 


Fig.  30.     Rabbit   brain.  Area  of  midbrain  showing  perivascular  infiltration 
with  round  cells.  Same  animal  as  Fig.  29  (Loewe  and  Strauss). 

proved  pathogenic  for  both  rabbits  and  monkeys  in  the 
later  generations.  This  would  tend  to  rule  out  the  possibility 
that  original  virus  carried  over  in  transplants  is  responsible 
for  the  potency  of  their  cultures.  This  fact  was  proved  by  a 
number  of   dilution   experiments  described  in  the  Journal 

14 


210 


ACUTE  EPIDEMIC  ENCEPHALITIS 


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ANIMAL  EXPERIMENTATION 


21  I 


of  Infectious  Diseases,  September,  1920.  In  connection  with 
our  animal  experiments,  we  wish  to  bring  out  that  we  have 
not  only  produced  typical  lesions  in  animals  with  cultures 
derived  from  virus  of  various  kinds,  but  we  have  also  been 


V        /  v 


•  at 


Fig.  31. — Rabbit  brain.  Section  of  midbrain  inoculated  intravenously  with 
organism  (Loewe  and  Strauss). 


able  in  many  instances  to  recover  the  organism  from  the 
brains  of  animals  so  injected  and  also  to  produce  lesions  in 
animals  injected  in  the  same  manner  with  control  cultures. 
Immunological  studies  are  now  in  progress.  These  include 
complement  fixation  studies  with  both  bacterial  and  virus 


212 


ACUTE  EPIDEMIC  ENCEPHALITIS 


antigens,  and  neutralization  experiments.  Neutralization  of 
both  virus  and  culture  by  means  of  convalescent  serum  from 
cases  of  epidemic  encephalitis  has  been  successful.  Both 
natural   and   acquired   immunity   in  animals   were   demon- 


-    *    .  /    V.  *    .       >•*         •      ■  >  "  ■*  -  *• *** 


'S^.*\ 


v-*v    . »  . «  -:%  •>    '/    - 


,* 


*T*  vv  j    •  ■   •  ,•  *****  *  m,  '-Mr  ♦*!.*     »««.   %  ^**  .     rf«*  %  4,»*M  **■ 


»«&*  •!!*>* 

Fig.  32. — Rabbit.  Section  of  spinal  cord  inoculated  intravenously  with  or- 
ganism. Same  animal  as  that  pictured  in  Fig.  31  (Loewe  and  Strauss). 

strated.  A  peculiar  phenomenon  is  chain  formation  when 
organisms  are  grown  in  convalescent  serum,  analogous  to  the 
so-called  Pfaundler  phenomenon  with  typhoid  bacilli. 

From  the  experimental  work  outlined  above  we  wish  to 
state  that  epidemic  encephalitis  is  due  to  a  living  specific 


ANIMAL  EXPERIMENTATION 


213 


infectious  agent,  different  from  that  of  poliomyelitis.  This 
stand  recently  has  been  indorsed  by  both  Levaditi  and 
Harvier,  and  Mcintosh  and  TurnbuII. 


Fig.  33. — Monkey  brain.  Section  of  midbrain  inoculated  intracranially  with 
organism  (Loewe  and  Strauss). 

Bibliography 

1.  Strauss,  Hirshfeld  and  Loewe.  N.  York  M.  J.,  19 19,  cix,  772. 

2.  Loewe,  Hirshfeld  and  Strauss.  J.  Inject.  Dis.,  1919,  xxv,  378. 

3.  Loewe  and  Strauss.  J.  Am.  M.  Assn.,  1919,  Ixxiii,  1056. 

4.  Loewe  and  Strauss.  J.  Am.  M.  Assn.,  1920,  Ixxiv,  1373- 

5.  Loewe  and  Strauss.  Proc.  New  York  Path.  Soc.,    1920,  xx, 

No.  1-5,  18. 


2i4  ACUTE  EPIDEMIC  ENCEPHALITIS 

6.  Loewe  and  Strauss.  J.  Inject.  Dis.,  1920,  xxvii,  No.  3,  250. 

7.  Levaditi  and  Harvier.  Compt.  rend.  Soc.  de  biol.,  Par.,  1920, 

Ixxxiii,  354;  also  1920,  Ixxxiii,  385;    Soc.    med.    des    hop.    de 
Paris,  1920,  179  and  583;  also  xliv,  876-880. 

8.  McIntosh  and  Turnbull.  Brit.  J.  Exper.  Path.,   1920,  i,  2; 

also  1920,  i,  No.  5,  257. 

9.  Ottolenghi,  D'Antona  and  Tonietti.  Policlin.,  Roma,  1920, 

xxvii,  No.  39,  1075. 

Cultivation  of  the  Virus  (Israel  Strauss).  The 
criticism  has  been  made  that  experimental  inoculations  with 
foreign  material  have  produced  lesions  in  rabbits.  The 
foreign  material  which  we  have  used,  as  shown  in  Dr. 
Loewe's  paper,  has  consisted  largely  in  filtrates;  at  times  in 
emulsions  and  at  other  times  in  cultures.  This  is  not  foreign 
material  in  the  sense  in  which  pathologists  use  the  term. 
The  amount  used  is  very  small.  The  filtrates  are  nothing  but 
filtrates  of  saline  solution.  The  emulsion,  of  course,  is  a 
foreign  substance  inoculated  into  an  animal,  but  you  will  note 
that  in  many  instances  we  used  controls — that  is,  we  inocu- 
lated emulsions  from  the  brains  of  individuals  dying  from 
other  diseases,  and  never  once  in  our  experience  did  we  find 
any  lesion  in  these  rabbits. 

We  have  also  inoculated  the  spinal  fluids  of  cases  suffering 
from  diseases  other  than  epidemic  encephalitis,  and  again 
never  once  in  all  the  rabbits  we  have  used  have  we  ever 
found  any  lesion.  We  have  also  used  the  nasal  mucous 
membranes — filtrates  of  people  suffering  from  diseases  other 
than  encephalitis,  and  again  never  found  a  lesion.  The  rabbit 
has  been  found  to  have  diseases,  especially  diseases  of  the 
vessels  similar  to  arteriosclerosis,  which  has  negatived  the 
work  done  in  the  production  of  arteriosclerosis  in  rabbits, 
but  I  know  of  no  other  lesion  of  any  importance  that  has 
been  found  by  experimental  workers  in  rabbits,  especially 
when  using  careful  methods,  which  is  like  that  produced 
by  our  inoculations. 

When  we  presented  this  paper  before  the  Society  of 
Pathologists  of  New  York  City,  not  a  single  individual  among 


ANIMAL  EXPERIMENTATION 


215 


W*^f\,W^^^ 


Fig.  34.  Rabbit  brain.  Cortex  of  cerebrum  showing  focal  infiltration  with 
round  cells  in  proximity  to  vessel  showing  mononuclear  cell  infiltration  of  the 
adventitia.  Rabbit  injected  with  same  inoculum  as  animal  pictured  in  Figs. 
29  and  30. 


2i6  ACUTE  EPIDEMIC  ENCEPHALITIS 

the  highly  trained  technical  men  present  made  any  objection 
on  this  basis.  In  his  discussion  of  our  paper  before  the 
Academy  of  Medicine  in  May,  Dr.  Flexner  who  had  failed 
to  reproduce  the  disease  in  monkeys  or  rabbits  described 
some  inoculations  made  with  a  view  of  determining  whether 
a  lesion  similar  to  encephalitis  could  be  produced  in  a  rabbit 
by  using  other  organisms.  He  succeeded  in  producing  a 
perivascular  infiltration,  by  the  use  of  an  attenuated  strepto- 
coccus viridans,  but  he  admitted  at  that  time  that  the 
lesions  produced  by  us  could  not  have  been  produced  by 
a  streptococcus  viridans  because  we  were  competent  enough 
in  our  bacteriological  methods  to  have  isolated  a  strepto- 
coccus viridans  had  such  an  organism  been  present  in  any  of 
our  fluids. 

Levaditi  and  Harvier  have  produced  in  rabbits  the  typical 
lesions  of  encephalitis  Iethargica  by  inoculating  rabbits  with 
emulsions  from  the  human  brain.  They  have  found  that  they 
could  inoculate  a  monkey  with  the  "virus  fixe"  obtained 
from  the  rabbit  inoculations.  They  also  succeeded  in  pro- 
ducing the  disease  in  guinea-pigs,  and  what  is  of  great 
importance  when  you  consider  this  question  of  foreign 
material,  they  had  produced  the  disease  in  rabbits  by 
inoculating  a  rabbit  in  the  sciatic  nerve  with  the  virus  fixe 
and  also  by  intraocular  inoculation.  They  have  confirmed 
our  work  in  transmitting  the  virus  from  the  nasal  pharyngeal 
mucous  membrane  of  human  beings  into  rabbits,  and  they 
found  out,  as  we  had  found  out,  that  not  only  was  the  nasal 
mucous  membrane  infective  for  rabbits  but  the  virus  could 
be  recovered  in  the  nasal  mucous  membrane  of  rabbits  that 
had  been  infected  intracranially;  in  other  words,  that  this 
was  both  the  method  of  ingress  and  also  of  egress.  They  had 
also  preserved  the  virus  in  the  testicle  of  a  rabbit  for  a 
number  of  days  and  they  found,  interestingly  enough,  that 
the  retina  of  animals  was  also  infectious. 

Their  conclusions  were  that  this  was  a  filtrable  virus  to  be 
preserved  in  glycerine  and  was  effective  for  both  rabbits  and 
monkeys,   and  can  be  rendered  a  virus  fixe  by  repeated 


ANIMAL  EXPERIMENTATION 


217 


+->       £,' 


218  ACUTE  EPIDEMIC  ENCEPHALITIS 

inoculations.  In  a  personal  comment  by  Levaditi  he  stated 
that  his  cultural  work  had  not  been  extensive  enough 
to  give  any  results,  and  furthermore  that  he  was  having 
trouble  with  the  serum  which  he  was  using.  It  may  interest 
you  to  know  that  he  sent  us  his  virus  and  that  we  have 
cultivated  the  organism  out  of  his  virus  and  have  it  now  in 
the  fourth  generation. 

In  England,  Mackintosh  and  TurnbuII  have  succeeded 
in  producing  the  disease  in  a  monkey  by  intracranial  inocu- 
lations of  the  emulsion  of  the  human  brain,  and  also,  again 
of  importance  regarding  this  criticism  regarding  the  use  of 
foreign  material,  by  inoculation  of  a  monkey  intraperiton- 
eally.  In  both  cases  their  monkeys  came  down  with  lesions 
which  Mcintosh  and  TurnbuII  describe  as  characteristic 
pathologically. 

Lastly,  Mcintosh  alone  has  recently  published  an  article 
in  which  he  states  that  he  has  produced  the  disease  in  a  series 
of  rabbits  and  also  a  monkey,  and,  interestingly  enough, 
also  describes  the  characteristic  lesion  in  a  monkey  which 
developed  a  spontaneous  infection.  The  monkey  having  been 
in  contact  with  the  monkey  which  he  had  inoculated,  came 
down  at  a  period  of  incubation  comparable  to  the  period  of 
incubation  of  the  monkey  inoculated. 

There  is  as  yet  no  confirmation  of  our  work  on  the  organ- 
ism. We  are  dealing  here  with  a  new  field  of  bacteriology,  the 
field  of  filtrable  organisms.  Some  years  ago  Foster  isolated 
a  filtrable  organism  from  cases  of  common  colds,  and  in 
Foster's  article  there  is  a  footnote  which  is  of  a  great  deal  of 
significance.  He  states  that  he  attempted  to  do  this  work 
after  reading  Noguchi's  description  of  his  method,  but  he 
found  he  was  unable  to  isolate  the  organism.  He  went  to  the 
Rockefeller  Institute,  and  he  states  that  in  order  to  do  work 
of  this  kind  one  has  to  study  under  the  master  himself, 
because  the  work  is  so  difficult  technically  and  is  open  to  so 
many  pitfalls  that  it  is  only  by  personal  instruction,  he 
thought,  that  one  can  acquire  the  method.  His  work  so  far 
as  I  know  has  not  been  confirmed. 


ANIMAL  EXPERIMENTATION 


219 


'*■  >%•''■' 


W,  '»4<& 


iff'  'JfryV»x&fij&    <&  "     *  "      '*. 


220  ACUTE  EPIDEMIC  ENCEPHALITIS 

The  next  piece  of  work  on  filtrable  viruses  is  that  of 
Flexner  and  Noguchi,  who  have  isolated  an  organism  from 
cases  of  poliomyelitis.  The  confirmation  of  their  work  has  as 
yet  not  been  general.  Yet  we  personally  believe  that  the 
organism  isolated  by  Flexner  and  Noguchi  is  the  etiological 
agent  of  poliomyelitis. 

It  is  interesting  to  note  that  Bradford  and  Wilson  in  their 
studies  of  infective  encephalitis  during  the  war  probably  had 
the  virus  and  isolated  it.  Then  they  made  cultural  studies 
which  Arkwright  criticised  because  he  found  that  the  organ- 
isms were  not  in  pure  culture,  and  they  admit  in  the  Ark- 
wright article  that  they  were  probably  wrong  in  assuming 
that  they  had  the  organism  in  pure  culture.  We  believe  our- 
selves that  they  probably  did  have  the  organism;  but,  as 
Arkwright  had  proved,  it  was  not  in  pure  culture.  They  made 
this  error  very  likely  because  of  their  unfamiliarity  with  the 
method. 

Our  work  is  the  latest  that  has  been  done  in  the  study 
of  filtrable  organisms.  We  are  indebted  extremely  to 
Noguchi  for  having  shown  us  the  way  and  the  method.  The 
finding  of  this  organism  does  not  in  itself  mean  as  much  to 
us  as  does  the  fact  that  we  feel  that  we  have  in  our  work 
placed  upon  record  for  bacteriologists  and  pathologists  for 
the  first  time  completely  the  fact  that  there  is  a  filtrable 
organism  as  a  cause  of  disease. 

The  following  questions,  submitted  to  Drs.  Loewe  and 
Strauss  before  the  Commission,  together  with  the  answers 
to  them,  are  here  reported  verbatim. 

Dr.  Dana:  Will  you  be  good  enough  to  tell  us  or  explain  the 
reasons  why  Dr.  Amoss  and  his  group  of  workers  did  not  get  the 
same  results  as  you  did? 

Dr.  Loewe:  His  results  are  practically  as  inexplicable  to  me 
as  to  the  gentlemen  gathered  here.  I  can  merely  say  that  in  order 
to  straighten  out  this  difficulty  an  invitation  was  extended  to  Dr. 
Amoss  to  come  up  and  work  with  us.  He  found  it  difficult  to  do  this, 


ANIMAL  EXPERIMENTATION  221 

so  we  attempted  to  compromise  by  having  him  run  duplicate 
experiments  with  our  materials  and  with  our  filters  and  by  having 
us  to  run  duplicate  experiments  with  his  filters  and  his  materials. 
In  other  words,  we  feel  that  his  negative  results  may  be  due  to 
failure  to  obtain  the  same  amount  or  the  same  quality  of  materials 
that  we  have  obtained,  or  we  feel  that  he  may  have  used  a  certain 
type  of  filter  which  we  have  not  used.  I  feel  that  is  the  only  expla- 
nation, and  we  would  welcome  Dr.  Amoss  coming  up  and  working 
with  us  in  order  to  straighten  out  the  difficulty. 

1  may  say  that  our  animal  experimentation  numerically  far 
exceeds  his,  so  far  as  he  cited  it  at  the  Academy  of  Medicine,  and 
in  all  our  inoculations  we  were  aware  of  a  50  per  cent  immunity  in 
rabbits,  and  we  therefore  used  series  of  animals.  We  did  not  spare 
animals  or  spare  materials.  I  do  not  think  he  had  as  many  autopsies 
as  we  were  fortunate  to  have.  We  had  twenty-four,  and  as  I  said, 
we  used  over  600  rabbits  and  over  40  monkeys. 

Dr.  Sachs  :  May  I  ask  you  to  make  some  statement  as  to  whether 
in  your  own  experiments  you  have  had  any  distinct  failures  and  what 
the  proportion  of  failures  has  been? 

Dr.  Loewe:  I  believe  I  mentioned  that  with  every  individual 
material  inoculated  we  had  so  many  positives  and  the  remainder 
were  negative.  That  varied  with  the  different  materials.  In  spinal 
fluids  our  inoculations  were  less  than  with  nasal  washings;  with 
the  brain  they  were  less  than  with  nasal  washings,  etc.,  and  our 
cultural  work  proportionately. 

Dr.  Dana  :  I  am  requested  to  ask  what  the  difference  is  between 
the  filter  used  by  Dr.  Amoss  and  by  yourself.  Do  you  know? 

Dr.  Loewe:  I  haven't  any  idea.  In  the  beginning  of  the  work 
I  can  merely  say  that  we  used  a  Berkefeld  filter,  but  owing  to  the 
exigencies  of  the  war,  etc.,  we  were  unable  to  obtain  the  original 
Berkefeld  filters  later  and  we  therefore  used  the  domestic  filters 
which  we  found  satisfactory  in  a  certain  proportion  of  cases.  We 
tested  our  filters  carefully  and  discarded  as  much  as  75  or  80  per 
cent  of  a  given  lot;  before  using  a  filter  we  were  careful  enough  to 
test  it  out  against  the  usual  test  organisms,  and  when  they  proved 
satisfactory  to  us  we  continued  our  experiments  with  those  par- 
ticular filters. 

Dr.  Taylor:  In  what  respect  do  you  regard  your  organism 
as  related  to  that  of  poliomyelitis?  In  the  first  place  do  you  regard 
it  as  a  specific  organism  or  possibly  as  a  different  strain  of  the 
organism  which  presumably  is  the  cause  of  infantile    paralysis? 


222  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Loewe:  We  feel  that  the  two  diseases  are  distinct;  just  as 
there  are  groups  of  streptococci  and  pneumococci  there  are  groups 
of  organisms  with  different  pathogenic  characteristics.  Culturally 
they  are  the  same  or  practically  the  same,  with  slight  differences 
which  do  not  amount  to  much  because  we  may  find  differences  in 
cultural  biological  characteristics  in  a  given  organism  and  given 
strain  at  different  times;  but  from  our  neutralization  experiments 
we  feel  that  the  organism  is  specific.  In  other  words,  we  have 
formed  neutralization  experiments  with  convalescent  serum  with 
both  virus  and  culture,  and  we  have  protected  animals  by  bring- 
ing the  culture  in  contact  with  the  convalescent  serum  for  a  certain 
length  of  time,  injecting  new  animals,  of  course,  and  controlling 
it  with  injections  of  virus  alone  into  the  animals. 

Dr.  Taylor:  In  your  animals  you  not  infrequently  got  lesions 
pathological  to  a  certain  extent  and  clinical  signs  which  were 
analogous  to  infantile  paralysis,  didn't  you? 

Dr.  Loewe:  We  got  paralytic  conditions. 

Dr.  Dana:  Was  there  any  other  case  of  apparent  contagion? 
With  regard  to  the  contagiousness  of  the  disease,  you  spoke  as 
though  one  animal  appeared  to  acquire  the  disease  through  contact 
with  another,  did  you  not? 

Dr.  Loewe:  I  believe  Dr.  Strauss  mentioned  the  literature  on 
that  subject.  We  personally  are  not  prepared  to  say  that  we  have 
had  any  contact  infections,  but  Mcintosh  describes  a  distinct 
contact  infection,  an  infection  which  can  only  be  ascribed  to  con- 
tact. In  other  words,  the  incubation  period  between  the  original 
inoculation  and  symptoms  in  one  monkey  and  the  symptoms  in 
another  monkey  one  would  only  ascribe  to  contact  infection. 
I  may  say  that  all  our  experimental  animals  were  isolated  and 
kept  in  cages  apart  from  normal  animals,  and  there  was  no  possi- 
bility of  contact  infection. 

Dr.  Neustaedter:  In  what  percentage  of  cases  in  monkeys  did 
you  have  anterior  horn  lesions  and  in  what  percentage  purely 
cerebral  lesions? 

Dr.  Loewe:  I  cannot  state  the  percentages.  I  can  only  recall 
two  animals  in  which  we  got  distinct  lesions  in  the  spinal  cord,  and 
even  in  those  two  animals  there  was  no  destruction  of  the  anterior 
horn  cells.  As  I  say  we  are  carrying  on  a  minute  comparative 
study  of  these  animals  which  we  are  prepared  to  publish  at  some 


ANIMAL  EXPERIMENTATION  223 

subsequent  date,  but  I  feel  sure  we  will  not  find  the  lesions  of 
poliomyelitis  in  our  experimental  animals.  Incidentally,  I  do  not 
believe  anybody  has  been  able  to  produce  the  lesions  of  poliomye- 
litis in  rabbits,  as  we  pointed  out.  Marks,  of  course,  has  inoculated 
rabbits  with  poliomyelitis  virus  and  subsequently  brought  down 
monkeys  with  them,  but  he  himself  claims,  and  rightly  so,  that 
the  rabbit  in  his  case  merely  acted  as  a  host  for  the  virus. 

Dr.  Strauss:  I  want  to  call  attention  to  one  part  of  the  work 
which  Dr.  Loewe  mentioned  and  which  is  new  and  extremely  signifi- 
cant. It  may  have  escaped  the  attention  of  the  Commission.  That 
is  the  intravenous  inoculation  of  this  organism  and  the  remarkable 
thing  that  it  showed  a  selective  affinity  for  the  brain.  These  animals 
died  after  an  intravenous  inoculation.  Now  regarding  this  contact 
infection  which  Dr.  Dana  has  asked  about,  Dr.  Loewe  has  for- 
gotten to  mention  something  of  which  we  are  not  exactly  certain 
as  yet.  As  we  stated,  we  have  kept  our  animals  isolated  with  one 
exception.  The  sheep  that  died  after  intravenous  inoculation  was  in 
the  same  pen  with  another  sheep,  and  this  second  sheep  has  died, 
and  our  autopsy  of  this  second  sheep  showed  us  nothing  but  a 
marked  degeneration  of  the  liver.  The  brain,  however,  has  not 
been  studied,  so  we  are  not  yet  prepared  to  state  whether  this 
second  sheep  has  come  down  with  encephalitis  or  not.  We  are 
anxiously  awaiting  the  results  ot  the  culture  studies  of  that  sheep's 
brain  because  it  may  be  that  we  likewise  have  got  a  contact  infec- 
tion. That  is  the  only  instance  in  which  two  animals  were  kept  close 
beside  each  other.  While  this  one  was  dying,  the  other  sheep  was 
beside  it  and  the  food  was  not  separated.  We  are  not  yet  prepared 
to  say  but  what  we  may  have  an  example  of  contact  infection 
there. 

Dr.  Thalhimer:  It  is  my  privilege  to  present  to  you  some 
cultural  and  experimental  studies  of  epidemic  encephalitis.  The 
main  value  which  these  results  might  have  is  that  they  are  con- 
firmatory of  the  work  which  have  been  reported  by  Dr.  Loewe  and 
Dr.  Strauss.  From  the  central  nervous  system  material  from  4 
fatal  cases  of  epidemic  encephalitis  has  been  available — spinal 
fluids  from  3  cases  which  I  have  completed  the  study  of  myself, 
and  from  a  fourth  spinal  fluid  the  results  of  which  I  heard  by  letter 
yesterday.  Two  oi  these  fatal  cases  were  of  the  fulminating  type 
that  died  within  thirty-six  hours.  One  of  the  spinal  fluids  was  from 
one  of  the  fulminating  cases;  one  was  from  a  convalescent  case  of 


224  ACUTE  EPIDEMIC  ENCEPHALITIS 

thejethargic  type — a  nurse  who  was  sick  in  a  hospital  in  Chicago. 
The  third  spinal  fluid  was  from  a  lethargic  soldier  at  the  Waukesha 
Hospital  for  Soldiers  near  Milwaukee.  Virus  from  the  central 
nervous  system  from  these  14  cases  has  been  injected  into  rabbits 
and  has  produced  the  disease — has  produced  the  microscopic  lesions 
of  the  disease,  and  this  virus  has  been  carried  through  ten  series 
of  animals. 

From  the  central  nervous  system  an  organism  has  been  recovered 
and  this  organism  is  filtrable  and  has  all  the  cultural  and  other 
characteristics  which  have  been  described  and  has  been  carried 
through  from  twelve  to  fourteen  generations.  Rabbits  inoculated 
intracranially  with  these  cultures  have  come  down  with  the 
disease.  The  organism  has  been  recovered  from  their  brain.  A 
large  number  of  animals  inoculated  with  the  virus  at  various 
stages  of  its  passage  have  been  cultivated  and  the  organism  has 
also  been  recovered  from  their  brains.  More  recently  guinea-pigs 
have  been  used — inoculated  intracranially  both  with  virus  and 
cultures — have  come  down  with  the  disease,  have  shown  a  micro- 
scopic lesion  and  the  organism  has  been  recovered  again  from  their 
brains. 

The  fourth  spinal  fluid  which  I  just  heard  from  was  obtained 
from  rather  a  peculiar  case.  The  animal  was  inoculated  intra- 
cranially and  died  fourteen  days  after  inoculation,  and  I  have  also 
heard  that  sections  of  the  brain  showed  a  typical  microscopical 
lesion.  In  other  words,  the  results  reported  by  Drs.  Loewe  and 
Strauss  of  the  filtrable  virus  obtainable  from  the  central  nervous 
system  of  spinal  fluid  have  been  confirmed  in  the  laboratory  at 
Columbia  Hospital,  Milwaukee.  A  filtrable  microorganism  has 
been  grown  from  this  material  on  the  perfected  medium  of  Noguchi. 
This  organism  has  been  injected  into  animals,  has  reproduced 
the  disease,  microscopic  lesions,  and  this  organism  has  again  been 
recovered  from  the  brains  of  these  animals. 

Immunological  Distinctions  of  Encephalitis  and 
Poliomyelitis  (Harold  L.  Amoss).  The  means  of  dis- 
tinguishing epidemic  poliomyelitis  and  lethargic  encephalitis, 
which  has  not  yet  been  applied,  relates  to  the  point  whether 
the  serum  of  convalescent  cases  of  lethargic  encephalitis 
can  neutralize  the  virus  of  pliomyelitis.  This  fact  is  readily 
determined   experimentally   by   the   method   described   by 


ANIMAL  EXPERIMENTATION  225 

Amoss  and  Eberson.1  The  principle  of  the  test  lies  in  the 
power  of  a  neutralizing  serum,  when  administered  intra- 
spinally,  to  prevent  the  development  of  poliomyelitis  in 
the  monkey  following  the  intravenous  injection  of  a  large 
dose  of  the  virus. 

The  blood  serum  of  4  cases  of  lethargic  cencephalitis  was 
used  in  the  test,  one  from  a  patient  convalescent  in  the 
fifth  week  of  the  disease,  the  second  in  the  fourth  month, 
the  third  in  the  fifth  month,  and  the  fourth  fifteen  months 
after  the  attack.  The  tests  were  controlled  by  two  experi- 
ments in  which  the  same  procedure  was  followed,  except 
that  one  monkey  received  intraspinal  injections  of  normal 
human  serum  and  the  other  intraspinal  injections  of  polio- 
myelitic  serum  from  a  monkey  which  had  had  experimental 
poliomyelitis  nine  months  before  and  recovered  with  residual 
paralyses. 

The  virus  of  poliomyelitis  used  came  from  a  strain  which 
had  been  passed  from  monkey  to  monkey  many  times  during 
the  past  nine  years  and  which,  between  passages,  had  been 
preserved  in  50  per  cent  glycerol  in  the  ice  box.  Before 
starting  the  tests,  this  virus  was  passed  through  three  normal 
monkeys  in  order  to  determine  its  virulence.2  The  certain 
infecting  dose  for  intracerebral  injection  was  found  to  be 
0.25  c.c.  of  a  Berkefeld  filtrate  of  a  5  per  cent  suspension  of 
the  nervous  tissues  containing  the  virus. 

The  infecting  power  of  the  virus  when  given  intravenously 
is  shown  in  the  following  preliminary  experiment. 

A  monkey  received  at  5  p.m.  an  intraspinal  injection  of  2  c.c. 
of  normal  horse  serum.  The  following  morning  50  c.c.  of  a  5  per  cent 
suspension  of  fresh  virus  were  given  intravenously.  Five  days  later 
the  animal  was  weak  in  both  legs  and  excited.  Both  arms  were 
paralyzed  on  the  sixth  day  and  the  monkey  died  on  the  seventh 
day. 

Autopsy.  Microscopic  lesions  of  experimental  poliomyelitis 
were  found. 

'Amos,  II.  L.,  and  Eberson,  F.  J.  Exper.  M.,  1918,  xxvii,  309. 

2  All  intracerebral  inoculations  were  made  under  ether  anesthesia. 


226  ACUTE  EPIDEMIC  ENCEPHALITIS 

In  making  suspensions  for  intravenous  injections  the 
tissues  used  must  be  fresh.  Accordingly,  a  monkey  prostrate 
from  an  intracerebral  injection  of  0.5  c.c.  of  a  suspension 
of  the  virus  six  days  before,  was  killed  with  ether  and 
autopsied  at  once.  A  5  per  cent  suspension  of  the  cord  and 
medulla  was  prepared  for  immediate  injection. 

Series  1 

Experiment  1.  Macacus  rhesus  A.  Normal  human  serum  con- 
trol. March  11,  1920,  5.50  p.m.,  injected  intraspinally  2  c.c.  of 
fresh  normal  human  serum.  March  12,  2.30  p.m.,  injected  intra- 
venously 50  c.c.  of  a  5  per  cent  suspension  of  fresh  poliomyelitis 
nervous  tissue.  2.50  p.m.,  intraspinal  injection  of  2  c.c.  of  fresh 
normal  human  serum.  The  intraspinal  injection  of  2  c.c.  of  normal 
human  serum  was  repeated  daily  for  three  days.  March  18th, 
excited;  slight  head  tremor  and  left  facial  paralysis.  March  19th, 
prostrate.  March  20th,  etherized  when  moribund. 

Autopsy.     Microscopic  lesions  of  experimental  poliomyelitis. 

Experiment  2.  Macacus  rhesus  B.  Immune  poliomyelitic 
serum.  March  n,  1920,  6  p.m.,  injected  intraspinally  2  c.c.  of 
serum  from  a  monkey  which  had  had  experimental  poliomyelitis 
nine  months  before  and  had  recovered  with  residual  paralyses. 
March  12,  3  p.m.,  injected  intravenously  50  c.c.  of  virus  suspension. 
3.25  p.m.,  intraspinal  injection  of  2  c.c.  of  poliomyelitic  immune 
monkey  serum.  The  intraspinal  injections  of  2  c.c.  of  immune 
monkey  serum  were  repeated  daily  for  three  days.  The  monkey 
remained  well. 

Experiment  3.  Macacus  rhesus  C.  Serum  from  convalescent 
case  of  lethargic  encephalitis.  March  11,  1920,  6.05  p.m.,  injected 
intraspinally  2  c.c.  of  serum  from  Case  1,  aged  thirty-one  years, 
who  was  in  the  fifth  week  of  well-defined  lethargic  encephalitis 
with  general  disturbance  of  the  functions  of  the  central  nervous 
system  and  involvement  of  third  and  seventh  cranial  nerves. 
March  12th,  3.30  p.m.,  intravenous  injection  of  50  c.c.  of  virus  sus- 
pension. 3.35  p.m.,  intraspinal  injection  of  2  c.c.  of  encephalitis 
serum  from  Case  1.  The  intraspinal  injection  of  the  encephalitic 
serum  was  repeated  daily  for  three  days.  March  17th.  Animal  slow 
and  weak.  March  18th.  Found  dead  at  9  a.m. 

Autopsy.     Microscopic  lesions  of  experimental  poliomyelitis. 


ANIMAL  EXPERIMENTATION  227 

Experiment  4.  Macacus  rhesus  D.  Serum  from  convalescent 
case  of  lethargic  encephalitis.  Mar.  11,  1920,  6.10  p.m.,  injected 
intraspinally  2  c.c.  of  serum  from  Case  2,  aged  thirty-four  years, 
three  months  after  definite  attack  of  lethargic  encephalitis  in 
which  there  was  general  disturbance  of  the  function  of  the  central 
nervous  system,  involving  the  third  and  seventh  cranial  nerves 
and  spinal  motor  roots.  March  12th,  4  p.m.,  intravenous  injection 
of  50  c.c.  of  virus  suspension.  5  p.m.,  injected  intraspinally  2  c.c. 
of  convalescent  encephalitis  serum  from  Case  2.  The  intraspinal 
injection  of  2  c.c.  of  encephalitic  serum  was  repeated  daily  for 
three  days.  March  18th.  Excited  and  ataxic.  March  19th.  Pros- 
trate. March  20th.  Etherized  when  moribund. 

Autopsy.     Microscopic  lesions  of  experimental  poliomyelitis. 

Series  2 

The  second  series  of  tests  carried  out  at  a  different  time 
was  controlled  by  an  experiment  in  which  normal  human 
serum  was  used  for  the  intraspinal  injections  as  in  Experi- 
ment 1.  The  procedure  in  this  series  was  the  same  as  in 
Series  1,  except  that  normal  horse  serum  was  used  for  the 
preparatory  intraspinal  injection  given  the  day  before 
the  intravenous  injection  of  virus.  The  same  strain  of  virus 
employed  in  Series  1  was  again  tested  for  infecting  power 
and  used  in  this  series. 

Experiment  5.  Macacus  rhesus  E.  Normal  human  serum  con- 
trol. May  18,  1920,  4.10  p.m.,  injected  intraspinally  2  c.c  of  nor- 
mal horse  serum.  May  19th,  12  m.,  intravenous  injection  of  50 
c.c.  of  virus  suspension.  12.25  p.m.,  injected  intraspinally  2  c.c. 
of  normal  human  serum.  The  intraspinal  injection  of  normal 
human  serum  was  repeated  daily  for  3  days.  May  23rd.  Monkey 
excited;  both  legs  weak.  May  24th,  complete  paralysis  of  both 
legs  and  right  facial  paralysis.  May  25th.  Died. 

Autopsy.     Microscopic  lesions  of  experimental  poliomyelitis. 

Experiment  6.  Macacus  rhesus  F.  Serum  from  case  of  leth- 
argic encephalitis.  May  18,  1920,  4  p.m.,  injected  intraspinally 
2  c.c.  of  normal  horse  serum.  May  19th,  11.30  a.m.,  intravenous 
injection  of  50  c.c.  of  virus  suspension.  11.55  a.m.,  intraspinal 
injection  of  2  c.c.  of  serum  from  Case  3,  aged  twenty-eight  years, 
15 


228  ACUTE  EPIDEMIC  ENCEPHALITIS 

taken  four  and  a  half  months  after  acute  onset  of  lethargic  en- 
cephalitis. The  patient's  illness  began  with  dizziness,  disturbance  of 
vision,  vomiting  and  fever,  and  he  gradually  became  stuporous. 
Later  paralyses  referable  to  the  seventh  and  spinal  nerves  ap- 
peared. The  intraspinal  injection  into  the  monkey  of  the  conva- 
lescent serum  was  repeated  daily  for  three  days.  May  26th,  monkey 
had  paralysis  of  both  arms  and  shoulder  muscles.  May  27th.  Died. 

Autopsy.     Microscopic  lesions  of  experimental  poliomyelitis. 

Experiment  7.  Macacus  rhesus  G.  Serum  from  case  of  lethargic 
encephalitis.  May  18,  1920,  4.20  p.m.,  injected  intraspinally  2  c.c. 
of  normal  horse  serum.  May  19th,  1 1  a.m.,  intravenous  injection  of 
50  c.c.  of  virus  suspension.  11.25  a.m.,  injected  intraspinally  2 
c.c.  of  serum  from  Case  4,  aged  twenty-four  years,  who  had  devel- 
oped lethargic  encephalitis  fifteen  months  before  and  was  still 
under  observation  with  residual  ptosis  and  partial  paralysis  of 
left  side  of  face  and  left  leg.  The  intraspinal  injection  into  the 
monkey  of  the  convalescent  encephalitis  serum  was  repeated  daily 
for  three  days.  May  24th,  monkey  had  double  ptosis.  May  25th, 
shoulder  muscles  paralyzed;  arms  and  legs  very  weak;  head  tremor; 
animal  almost  prostrate.  May  26th.  Died. 

Autopsy.     Microscopic  lesions  of  experimental  poliomyelitis. 

The  experiments  here  reported  show,  the  two  diseases 
can  be  distinguished  through  the  power  of  blood  serum  under 
certain  circumstances  to  neutralize  the  virus  of  poliomye- 
litis. The  blood  serum  of  convalescent  cases  of  poliomyelitis 
whether  in  man  or  monkey  possesses  this  neutralizing  power, 
while  the  blood  serum  of  recently  convalescent  cases  of 
epidemic  encephalitis  is  devoid  of  it. 

On  the  basis  of  the  distinguishing  characters  described, 
it  is  regarded  as  desirable  at  the  present  time  to  hold  epidemic 
poliomyelitis  and  epidemic  encephalitis  as  integrally  distinct 
affections.  The  latter  also  may  be  infectious,  yet  the  main 
lesions  of  poliomyelitis  are  present  in  the  spinal  cord,  and  of 
epidemic  encephalitis  in  the  midbrain. 

The  following  questions  submitted  to  Dr.  Amoss  before 
the  Commission,  together  with  the  answers  to  them,  are 
here  reported  verbatim. 


ANIMAL  EXPERIMENTATION  229 

Dr.  Tilney:  Would  you  be  good  enough  to  discuss  a  little  more 
in  detail  why  you  selected  the  in  vivo  method  in  preference  to  the 
in  vitro? 

Dr.  Amoss:  The  in  vitro  method  depends  upon  the  following 
experiment.  You  take  2  c.c.  of  the  serum  and  add  to  it  2'  m.l.d.'s 
of  your  virus;  let  it  set  in  the  incubator  for  two  hours  and  over- 
night in  the  ice  box,  and  inject  the  whole  mixture  in  the  monkey. 
If  you  will  take  a  series  of  these — I  have  done  I  think  20  at  one 
time,  using  the  same  serum — say,  using  5  monkeys  on  one  serum, 
you  will  find  that  some  of  the  monkeys  come  down  and  some  do 
not.  Whether  it  is  a  question  of  hydrogen-ion  concentration  or 
whether  it  is  a  question  of  the  variation  in  the  immune  bodies,  one 
can't  tell.  So  they  are  not  clear-cut  experiments.  Some  of  them 
will  come  down  and  some  will  not.  Another  thing — normal  human 
serum  will  sometimes  neutralize  in  vitro,  but  normal  human  serum 
never  neutralizes  in  vivo. 

Dr.  Barker:  Keeping  in  mind  the  possibility  that  the  virus 
of  encephalitis  might  be  a  modification  of  the  virus  of  poliomy- 
elitis— the  modification  going  so  far  as  to  involve  also  production  of 
diphenyl  bodies — is  there  anything  known  in  immunology  that 
would  correspond  to  that  possibility? 

Dr.  Amoss:  There  is  only  one  analogy  which  occurs  to  me  now. 
I  do  not  know  if  there  are  any  others.  If  you  take  a  pneumococcus 
type  2,  pneumococcus  type  2  serum  will  agglutinate  pneumococcus 
type  2  in  the  sub-groups  A  and  B.  Pneumococcus  type  2-A  will 
not  agglutinate  a  type  2  but  will  agglutinate  only  type  2-A,  and 
so  monotypical  type  2-B  will  agglutinate  only  type  2-B  and  will 
not  agglutinate  type  2-A  or  type  2.  That  is  the  only  group.  It 
may  be  that  it  is  perfectly  possible  from  that  analogy  that  enceph- 
alitis might  be  the  more  inclusive  from  an  etiological  stand- 
point and  that  poliomyelitis  might  correspond  to  type  2-A  or 
type  2-B  but  I  do  not  believe  it. 

Dr.  Timme:  Dr.  Thalhimer,  would  you  like  to  put  any  questions 
to  Dr.  Amoss  regarding  the  various  discrepancies  or  findings  in 
your  respective  work. 

Dr.  Thalhimer:  I  do  not  think  there  are  any  questions  that 
can  be  put  at  this  particular  time.  The  state  of  affairs  is  that  there 
were  simply  two  series  of  experiments  done — on  the  one  hand 
in  a  number  of  different  laboratories  with  positive  results  with 
microscopic  lesions  and  with  the  recovery  of  an  organism,  and  a 


23o  ACUTE  EPIDEMIC  ENCEPHALITIS 

series  of  experiments  by  Dr.  Amoss  of  the  Rockefeller  Institute 
with  negative  results.  I  do  not  think  there  are  any  questions  coming 
up  between  the  two  at  present.  I  think  the  only  thing  that  is 
indicated  is  that  with  this  divergence  a  suggestion  is  in  order  that 
these  two  series  of  workers  in  some  way  come  together  and  com- 
pare their  technique  and  compare  their  results,  and  see  if  there 
might  not  be  between  them  in  a  technical  way  some  differences 
which  can  be  eradicated.  The  work  has  got  to  stand  or  fall  as  it 
becomes  more  generally  verified  or  not,  and  I  think  that  the 
immediate  thing  to  be  done — being  as  there  are  sufficient  number 
of  people  interested  in  this  disease  to  come  to  these  meetings — is  to 
ask  Dr.  Amos  if  he  will  attempt  to  come  together  and  go  over 
this  with  Dr.  Strauss  or  myself,  and  see  if  we  cannot  evolve  some- 
thing which  is  worth  while  in  an  experimental  manner. 

Dr.  Sachs:  May  I  ask  Dr.  Thalhimer  whether  he  knows  if 
encephalitis  immunity  studies  have  begun? 

Dr.  Thalhimer:  Yes,  the  immunity  studies  have  been  begun  at 
Mt.  Sinai  Hospital. 

Dr.  Sachs:  There  is  a  question  handed  in  here:  Is  it  true  that 
the  disease  complex  of  poliomyelitis  cannot  be  reproduced  in 
rabbits  while  an  encephalitic  process  of  encephalitis  Iethargica 
can  be  produced  in  some  animals. 

Dr.  Amoss:  It  is  a  question  whether  or  not  poliomyelitis  has 
been  transmitted  to  rabbits.  Rosenauer  and  Caven  thought  that 
they  were  able  to  transmit  the  disease  to  rabbits,  and  Marks 
about  eight  years  ago  thought  he  had  been  able  to  transmit 
poliomyelitis  to  rabbits.  However,  in  view  of  the  findings  in  normal 
rabbits  which  I  reported  a  while  ago,  and  in  view  of  the  experi- 
ments by  Clark  and  some  of  the  rest  of  us  at  the  Rockefeller 
Institute,  I  do  not  believe  that  anybody  has  ever  transmitted 
poliomyelitis  to  rabbits.  We  have  taken  young  rabbits,  as  young 
as  you  can  inject  them  and  let  them  live,  and  we  have  gone  further 
and  given  them  massive  doses  of  x-ray  so  as  to  reduce  their 
lymphocytes.  Now  we  know  that  if  you  ray  monkeys  so  that  the 
lymphocytic  curve  comes  down  about  200  to  600  round  cells 
per  cubic  millimeter,  those  animals  are  much  more  susceptible 
to  poliomyelitis,  but  not  so  rabbits.  So  I  think  it  is  not  established 
that  rabbits  will  take  experimental  poliomyelitis. 

lMMUNOLOGICALrSTUDIEs"oF^EpiDEMIC  ENCEPHALITIS  AND 
POLIOMYELITS     (MARCUS    NeUSTAEDTER,    JOHN    H.   LaRKIN 


ANIMAL  EXPERIMENTATION  231 

and  E.  J.  Banzhaf).  It  is  a  well  established  fact,  as  was 
shown  by  Flexner  and  Lewis,  Netter  and  Levaditi,  Roemer, 
and  Anderson  and  Frost,  that  serum  of  patients  recovered 
from  poliomyelitis  neutralizes  virus  of  poliomyelitis  in  vitro 
and  also  protects  monkeys  from  the  disease  when  injected 
with  such  a  mixture.  It  is  also  known  that  normal  human 
serum  does  not  as  a  rule  neutralize  the  virus. 

Following  are  the  protocols  of  experiments : 

Experiment  1.  March  6,  1920.  Maccacus  A  was  injected  intra- 
cerebrally  with  0.5  c.c.  of  a  mixture  ot  poliomyelitis  virus  and 
serum  of  patient  Miriam  S.,  aet.  16  years,  three  months  after 
recovery  from  lethargic  encephalitis,  prepared  in  the  following 
manner: 

0.125  c.c.  of  a  5  per  cent  suspension  of  brain  and  cord  of  a 
monkey  that  died  of  poliomyelitis,  obtained  through  the  courtesy 
of  Dr.  Amoss  from  the  Rockefeller  Institute,  were  mixed  with  1.25 
serum  of  the  above  patient  and  incubated  at  370  for  two  hours 
and  kept  in  the  refrigerator  for  twenty  hours. 

Result.  The  animal  remained  well  without  any  visible  ill 
effects  until  April  21st,  when  it  was  found  dead.  The  autopsy 
showed  that  the  cause  of  death  was  tuberculosis. 

Control.  Maccacus  B  was  injected  in  the  same  manner  with 
0.5  c.c.  of  a  mixture  of  the  same  virus  and  in  the  same  proportion 
with  normal  adult  serum  prepared  as  above. 

Result.  The  animal  became  paralyzed  on  the  eighth  day  in  the 
right  upper  and  lower  extremities  but  survived  until  October  when 
it  was  anesthetized  and  autopsied. 

Experiment  2.  May  18,  1920.  Maccacus  E  was  injected  intra- 
cerebrally  with  1  c.c.  ot  a  mixture  of  equal  parts  of  a  5  per  cent 
suspension  of  Rockefeller  Institute  poliomyelitis  virus  and  serum 
of  patient  Dawe  J.,  aet.  30,  recovered  from  lethargic  encephalitis 
since  February  20,  1920.  This  mixture  was  incubated  at  370  for 
1  hour  and  20  minutes  and  kept  on  ice  for  ig}i  hours. 

Result.     The  animal  remained  perfectly  well  until  August  25th. 

Control.  Maccacus  D  was  injected  in  the  same  manner  with 
1  c.c.  of  a  mixture  of  equal  parts  of  the  above  virus  and  normal 
adult  serum  prepared  as  above. 

Result.  May  24th,  the  animal  found  ill  sitting  in  a  corner  of  the 
cage;  May  25th  paralysis  in  all  four  extremities  and  muscles  of  the 


232  ACUTE  EPIDEMIC  ENCEPHALITIS 

neck;  shallow  respiration.  Anesthetized  and  autopsied.  Macro- 
scopical  and  microscopical  changes  characteristic  of  poliomyelitis. 

Experiment  3.  June  22,  1920.  Maccacus  F  injected  intraspinally 
with  4  c.c.  of  a  mixture  of  equal  parts  of  a  2}^  per  cent  suspension 
of  virus  of  monkey  D  and  serum  of  Dr.  G.,  aet.  55  years,  suspected 
of  having  had  lethargic  encephalitis,  still  having  a  paralysis  of  facial 
nerve  with  complete  reaction  of  degeneration.  This  mixture  had 
been  incubated  at  370  for  2  hours  and  kept  on  ice  for  22  hours. 

Result.     The  animal  remained  well  up  to  November  5th. 

Control.  Maccacus  G  was  injected  as  above  with  4  c.c.  of  the 
same  virus  mixed  with  equal  parts  of  normal  NaCI  solution,  and 
incubated  as  above. 

Result.     June  28th,  the  animal  ill,  refuses  food. 

June  29th  paralyzed  in  all  four  extremities  and  muscles  of  the 
neck.  Anesthetized  and  autopsied.  Macroscopical  and  microscopical 
changes  typical. 

Experiment  4.  October  8,  1920.  Maccacus  K  was  injected 
intracerebrally  with  1.5  c.c.  of  a  mixture  of  equal  parts  of  an  8 
per  cent  suspension  of  poliomyelitis  virus  of  Maccacus  E  and  serum 
of  patient  from  Dr.  Foster  Kennedy's  service  in  Bellevue  Hospital, 
who  had  recovered  from  lethargic  encephalitis.  The  mixture  was 
incubated  for  2  hours  at  370  and  kept  in  the  refrigerator  for  22 
hours. 

Result.     The  animal  suffered  no  ill  effects  and  is  well  today. 

Control.  Maccacus  L  was  injected  with  1.5  c.c.  of  a  mixture 
of  equal  parts  ot  the  above  virus  suspension  and  serum  of  a  normal 
adult,  prepared  as  above. 

Result.  October  14th,  animal  very  ill;  left  upper  extremity  par- 
etic; October  16th.,  both  hind  limbs  paretic;  October  19th,  animal 
recovered  from  pareses  and  is  well  today. 

Experiment  5.  October  28,  1920.  Maccacus  M  injected  intra- 
cerebrally with  1.5  c.c.  of  a  mixture  of  equal  parts  of  a  10  per  cent 
suspension  of  poliomyelitis  virus  of  Maccacus  E  and  serum  of 
patient  Mary  S.,  aet.  16  years,  from  the  service  of  Dr.  Foster 
Kennedy  at  Bellevue  Hospital,  and  originally  observed  and 
described  by  Dr.  Tilney  as  Case  IV  in  his  book,  "Epidemic 
Encephalitis."  The  patient  is  at  present  in  the  neurological  service 
of  the  City  Hospital.  This  mixture  was  incubated  at  370  for  2 
hours  and  kept  on  ice  for  22  hours. 

Result.     The  animal  remained  well. 


ANIMAL  EXPERIMENTATION 


^33 


COMPARATIVE       RESULTS      IN      NEUTRALIZATION     TESTS      OF      POLIOMYEILTIS 

VIRUS      WITH      SERUM      OF      PATIENTS     CONVALESCENT      FROM 

POLIOMYELITIS    AND   LETHARGIC   ENCEPHALITIS 


Monkeys  Injected 


Result 


Flexner 

and 
Lewis 


5  poliomyelitis  virus  +  human  con- 
valescent polimyelitis  serum 

3  poliomyelitis  virus  +  human  sus- 
pected poliomyelitis  serum 

7  and  9  injections  of  poliomyelitis 
virus  +  normal  human  serum  of 
adults  and  children 


4  protected 

1  paralyzed,  living 

1  protected 

2  paralyzed  and  died 

3  paralyzed  and  died 
3    protected 

1  died,  no  paralysis  and  no 
poliomyelitis  lesions 


Netter 

and 

Levaditti 


4  poliomyelitis  virus  +  human  con- 
valescent poliomyelitis  serum 

1  control,  poliomyelitis  virus  +  nor- 
mal salt  solution 

3  poliomyelitis  virus  +  human  con- 
valescent poliomyelitis  serum 

1  control,  poliomyelitis  virus  +  nor- 
mal human  serum 


4  protected 

1  paralyzed  and  died 

3  protected 

1  paralyzed  and  died 


R< 


3  poliomyelitis  virus  +  human  con- 
valescent poliomyelitis  serum 

1  control,  poliomyelitis  virus  +  nor- 
mal salt  solution 

3  poliomyelitis  virus  +  human  con- 
valescent poliomyelitis  serum 

1  control,  poliomyelitis  virus  +  nor- 
mal new  born  infant  serum,  intra- 
cerebrally,  and  5  c.c.  pure  virus  in- 
traperitoneally 

2  controls,  poliomyelitis  virus  +  nor- 
mal new  born  infant  serum 


3  protected 

1  paralyzed  and  died 

3  protected 

1  paralyzed  and  died 


1    slightly    paretic,    recov- 
ered 
1  paralyzed  and  died 


Anderson 

and 

Frost 


1  poliomyelitis  virus  +  human  con- 
valescent poliomyelitis  serum 

10  poliomyelitis  virus  -f-  human  sus- 
pected poliomyelitis  serum 

10  controls,  poliomyelitis  virus  +  nor- 
mal human  serum 


1  protected 

7  protected 

1  paralyzed  and  died 

2  paralyzed,  survived 

3  protected 
7  paralyzed 


Authors' 
cases 


5  poliomyelitis  virus  +  human  con- 
valescent lethargic  encephalitis 
serum 

4  controls,  poliomyelitis  virus  +  nor- 
mal human  adult  serum 

1  control,  poliomyelitis  virus  -f-  nor- 
mal salt  solution 


5  protected 


1  paralyzed  and  dying 

1  paralyzed,  survived 

2  paretic,  recovered 

1  paralyzed  and  dying 


AH  sera  were  Wassermann  negative. 


234  ACUTE  EPIDEMIC  ENCEPHALITIS 

Control.  Maccacus  N  was  injected  in  the  same  manner  with 
1.5  c.c.  of  a  mixture  of  the  above  virus  suspension  and  equal  parts 
of  serum  of  an  eighteen  year  old  laboratory  helper,  who  claimed 
never  to  have  been  ill. 

Result.  November  2nd,  the  animal  was  ill  and  paretic  in  the 
right  upper  extremity  and  showed  also  a  slight  hypotonia  in  the 
right  lower  extremity.  The  same  condition  prevails  today. 

Experiment  6.  In  order  to  establish  whether  the  protection 
afforded  the  animals  was  due  to  the  use  of  the  convalescent  enceph- 
alitis serum,  Maccacus  E  was  injected  intracereb rally  with  1 
c.c.  of  a  5  per  cent  suspension  of  brain  and  cord  of  Maccacus  G 
on  August  25th,  about  three  months  after  the  initial  injection. 

Result.  August  31th,  the  animal  was  found  paralyzed  in  all 
extremities  and  dying.  Macroscopic  and  microscopic  changes  were 
characteristic  of  poliomyelitis. 

All  sera  used  proved  Wassermann  negative  and  the 
serum  of  a  different  person  was  used  as  a  control  in  each 
experiment. 

Five  monkeys  were  completely  protected  from  polio- 
myelitis by  sera  of  patients  convalescent  from  4  undoubted 
cases  and  one  suspected  case  of  lethargic  encephalitis. 

The  results  compare  favorably  with  the  results  of  other 
investigators  in  the  neutralization  experiments  of  polio- 
myelitis virus  and  convalescent  human  poliomyelitis  sera. 

It  is  concluded  from  these  facts  that  there  is  a  close  point 
of  contact  between  lethargic  encephalitis  and  poliomyelitis. 

BIBLIOGRAPHY 

1.  Flexner  and  Lewis,  quoted  by  Peabody,  Draper  and  Douchez. 

Monograph  4,  of  the  Rockefeller  Institute,  1912,  16. 

2.  Netter    and    Levaditti.    Compt.    rend.   Soc.   de   biol.,    Par., 

1910,617,855. 

3.  Roemer.  Die  epidemische  Kinderlaehmung,  Berlin,  191 1. 

4.  Anderson  and  Frost.  J.  Am.  M.  Assn.,  191 1,  Ivi,  663. 

The  following  questions,  submitted  to  Dr.  Neustadter 
before  the  Commission,  together  with  the  answers  to  them, 
are  here  reported  verbatim. 


ANIMAL  EXPERIMENTATION  235 

Dr.  Dana:  Why  will  you  not  draw  some  conclusions? 

Dr.  Neustaedter:  I  believe  that  before  we  could  draw  any 
definite  conclusions  two  other  things  ought  to  be  done,  which  I 
am  in  process  of  working  on.  One  is  to  test  out  the  spinal  fluids  of 
so-called  lethargic  patients  with  poliomyelitis  virus  for  complement 
fixation.  I  have  been  doing  that  for  the  last  few  months  in  frank 
cases  but  I  have  not  sufficient  number  to  draw  any  conclusions. 
Results  are  so  far  very  encouraging.  Another  experiment  that  I 
want  to  make  and  that  I  spoke  to  Dr.  Strauss  about  some  time 
ago  was  the  antipoliomyelitis  horse  serum  that  neutralizes  virus 
in  much  greater  proportions.  That  is,  the  poliomyelitis  horse 
serum  neutralizes  poliomyelitis  virus  in  proportions  of  one  to  two; 
two  of  virus  to  one  serum.  1  want  to  cross  the  experiment  and  try 
the  virus  of  encephalitis,  as  they  have,  and  neutralize  that  with 
our  serum  which  we  know  neutralizes  in  every  instance,  without 
exception,  poliomyelitis  virus.  When  I  have  those  three  factors 
together  I  believe  it  will  give  us  greater  encouragement  to  draw 
conclusions  than  at  the  present  time. 

Dr.  Dana:  As  I  understand  it,  you  state  that  the  serum  from 
convalescent  encephalitis  cases  neutralized  the  poliomyelitic 
monkey.  Do  you  infer  from  that  that  the  diseases  must  be  very 
closely  identical? 

Dr.  Neustaedter:  I  would  say  there  is  a  close  contact  between 
the  two.  I  would  not  say  anything  further  than  that.  I  believe  there 
is  a  close  contact  between  the  two;  whether  it  is  another  phase  or 
what  it  is,  I  am  not  prepared  to  say. 

Dr.  Dana:  May  there  not  be  many  other  infectious  diseases  the 
convalescent  serum  from  which  might  do  the  same? 

Dr.  Neustaedter:  That  has  been  tried,  as  far  as  I  know,  again 
and  again,  and  never  succeeded. 

Dr.  Dana:  You  could  say  that  some  other  convalescent  serum 
than  that  of  encephalitis  or  poliomyelitis  neutralizes  the  virus 
of  poliomyelitis,  couldn't  you? 

Dr.  Neustaedter:  Other  infectious  diseases  such  as  measles, 
scarlet  fever,  etc.,  have  been  tried  and  did  not  do  it,  but  we  do 
know  that  from  the  results  of  other  investigators  the  serum  of 
socalled  normal  people  has  neutralized  the  virus,  and  in  my  ex- 
periments here  two  controls  became  ill  but  recovered.  So  you  see 
normal  human  sera  also  contain  some  principles  evidently  that 
protect  the  monkey  to  a  certain  extent. 


236  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Patrick:  In  the  case  of  the  physician,  how  long  had  this 
physician  had  the  facial  palsy  before  you  saw  him? 
Dr.  Neustaedter:  A  week. 

Physiologic  Knowledge  as  Related  to  Syndromes 
of  Epidemic  Encephalitis  (Frank  H.  Pike).  On  our 
hypothesis  of  localization,  a  lesion  of  any  particular  group  of 
cells  should  produce  a  definite  effect.  One  asks  whether  or 
not  these  lesions  in  encephalitis  are  of  the  nature  of  deficiency 
lesions,  the  effects  being  such  as  one  might  get  from  excision 
of  definite  parts  of  the  nervous  system  without  inflammatory 
conditions  or  irritating  conditions  afterward,  or  whether  these 
are  of  the  nature  of  irritative  lesions. 

Some  years  ago  Stewart  and  Pike  in  animal  experimenta- 
tion tied  off  the  blood-vessels  to  the  brain  for  a  short  period 
of  time,  say  eight  to  ten  minutes,  and  observed  the  effects. 
There  were  convulsions  and  rigidity  which  might  persist 
for  three  or  four  days.  In  case  of  recovery  these  would  grad- 
ually pass  off.  These  cases  were  done  aseptically  and  con- 
ditions verified  at  autopsy.  At  that  time  at  least  no  changes 
were  found  which  suggested  encephalitis  or  meningitis.  In 
these  cases  as  was  shown  afterward  there  was  always  a 
chromatolysis.  The  cells  were  diffusely  stained  and  this 
change  was  found  at  times  to  persist  for  days  after  recovery. 

The  question  was  raised  as  to  whether  the  chromatolysis 
itself  might  have  been  sufficient  to  account  for  the  rigidity, 
and  perhaps  for  the  convulsions.  It  seems  to  be  pretty  sure 
that  some  agents  at  least  which  act  injuriously  upon  nerve 
cells  or  nerve  fibers  will  increase  their  excitability.  It  is 
known,  of  course,  that  there  is  an  action  current  produced 
at  every  beat  of  the  heart,  yet  the  phrenic  nerve  on  the  left 
side  runs  right  in  contact  with  the  pericardium.  There  is 
no  twitching  of  the  diaphragm  ordinarily.  The  threshold 
of  stimulation  of  this  phrenic  nerve  is  too  high  to  be  excited 
by  the  action  current  of  the  heart.  Yet  by  decreasing  the 
oxygen  supply,  by  decreasing  the  blood  supply  of  this  phrenic 
nerve,    it   is   perfectly   possible   to    demonstrate   that   the 


ANIMAL  EXPERIMENTATION  237 

diaphragm  on  the  left  side  twitches  at  each  beat  of  the  heart. 
It  seems,  therefore,  pretty  sure  that  there  are  conditions 
which  will  increase  the  actual  excitability  of  nerve  fibres 
and  also  of  nerve  cells. 

Now,  until  we  know  more  of  the  effects  of  toxins  upon 
nerve  cells,  one  must,  if  he  keeps  within  the  limits  of  veracity, 
be  extremely  brief.  Many  of  the  claims  that  have  been  made 
for  a  specific  action  of  toxins  upon  various  parts  of  the  ner- 
vous system  are  not  very  well  founded.  The  effects,  or  the 
supposed  effects,  of  pneumonia  toxin,  which  is  probably  the 
most  prominent,  and  perhaps  also  diphtheria  toxin  has  been 
shown  to  lie  in  the  end  organs  perhaps  more  than  in  the 
central  system. 

One  point  perhaps  is  the  relation  of  the  ectasis  of  the  blood 
to  the  lethargy.  Experimentally,  of  course,  we  can  reduce  the 
blood  supply  to  the  brain  to  almost  any  desired  degree.  It  is 
perfectly  possible  to  tie  up  both  carotid  and  both  vertebral 
arteries  in  a  cat  or  a  dog,  and  most  dogs  will  live  after  that, 
but  during  the  period  of  associated  lethargy  we  often  find  that 
there  are  convulsions.  We  find  great  respiratory  disturbances 
as  well,  and  within  the  last  two  years  we  have  found  that  in 
every  case  of  this  kind  which  we  tried  experimentally  there 
are  characteristic  changes  in  the  carbon  dioxide  and  oxygen 
concentration  of  the  blood.  Just  as  soon  as  one  reduces  the 
volume  of  blood  flowing  through  the  brain,  just  so  soon 
will  one  reduce  the  concentration  of  carbon  dioxide  in  the 
blood  and  increase  the  concentration  of  oxygen. 

From  this  point  of  view  then,  if  ectasis  is  the  only  thing 
concerned  in  the  production  of  lethargy,  one  would  expect 
certain  respiratory  changes,  and  also  certain  circulatory 
changes.  When  the  nerve  cells  are  uninjured  and  one  simply 
reduces  the  blood  supply,  there  is  a  prompt  rise  in  the  sys- 
temic blood-pressure,  and  we  have  shown  also  that  the  usual 
relation  exemplified  by  Marey's  law  in  the  high  blood- 
pressure  and  low  heart  rate  may  be  departed  from  here. 
We  get  a  dissociation  of  response.  We  may  get  a  rapid  heart 
rate  along  with  a  high  blood-pressure.  Stasis  may  in  part 


238  ACUTE  EPIDEMIC  ENCEPHALITIS 

account  for  this  lethargy,  particularly  in  view  of  the  peri- 
vascular infiltration  which  has  been  described,  but  one  should 
be  inclined  to  attribute  a  part  of  this  lethargy  at  least  to 
some  other  cause. 

The  muscular  rigidity  in  some  cases  at  least  departs  some- 
what from  the  conditions  we  get  experimentally.  Sherrington 
and  others  have  shown  that  in  lesions  of  the  cerebrum  we 
get  a  typical  rigidity  of  the  muscles,  a  decerebrate  rigidity. 
This  affects  the  extensor  muscles.  In  some  cases  of  epidemic 
encephalitis  there  is  a  pretty  general  rigidity  of  extensors 
as  well  as  flexors.  This  would  seem  to  differentiate  the  effects 
in  encephalitis,  so  far  as  our  experimental  knowledge  goes, 
from  the  effects  of  a  pure  cortical  lesion. 

It  has  been  somewhat  difficult  for  one  to  see  just  how  a 
lesion  of  the  endocrine  system  could  produce  such  opposite 
effects  as  have  been  described.  One  can  hardly  see,  for  in- 
stance, how  a  low  blood-pressure  and  profuse  sweating  might 
be  due  to  the  action  of  adrenalin  since  the  action  of  the 
sweat  gland  is  due  to  the  sympathetic  nervous  system.  It 
has  been  shown  experimentally,  as  it  had  previously  been 
postulated  clinically,  that  there  is  a  cortical  mechanism  for 
the  secretion  of  sweat.  One  would  like  to  know  whether  in 
these  cases  in  which  profuse  sweating  has  been  observed 
the  lesions  seem  to  be  more  of  the  cortical  type  or  whether 
they  were  confined  to  the  region  of  the  aqueduct,  as  seems  to 
be  the  rule.  We  are  inclined  to  think  that  we  have  an  irrita- 
tive process  here  as  exemplified  by  the  muscle  tonus,  and 
by  certain  of  the  other  disturbances,  namely,  that  of  the 
sweat  glands. 

One  or  two  observations  which  have  been  made  on  animals 
might  be  mentioned.  A  dog  developed  the  disease  known  as 
distemper  among  dogs,  but  there  was  a  recovery.  There  was  a 
twitching  of  all  four  limbs  persisting  even  during  sleep  at 
times.  This  continued  for  about  twenty-five  months  after 
the  attack.  There  was  a  similar  dog  up  in  the  Harvard 
Laboratory  where  there  was  this  same  twitching  of  the 
muscles,  but  it  was  more  severe.  Experiments  were  done  to 


ANIMAL  EXPERIMENTATION  239 

see  where  some  of  these  movements  came  from.  The  first 
thing  was  the  exposure  of  the  lumbar  cord  and  the  sections 
of  the  dorsal  roots  of  the  spinal  nerves  on  one  side.  If  these 
things  were  due  to  afferent  impulses  a  section  of  the  dorsal 
roots  should  have  some  effect.  Perhaps  the  twitchings  were 
somewhat  decreased  for  a  week  or  two,  but  they  returned 
again,  and  people  who  saw  the  dog  and  who  did  not  know 
on  which  side  the  nerve  roots  had  been  sectioned  were 
unable  to  tell  any  particular  difference  in  the  two  sides.  Fol- 
lowing that  was  extirpated  a  motor  area  on  one  side.  If  this 
was  due  to  cortical  irritation,  extirpation  of  the  motor  area 
should  have  some  effect.  The  dog  died  of  hemorrhage  in  a 
few  hours,  but  in  the  time  the  dog  survived,  one  couldn't 
see  that  there  was  any  marked  effect  on  the  twitchings  on  the 
two  sides.  It  seemed  to  be  distinctly  due  to  something  outside 
of  the  cerebral  cortex. 

The  following  questions,  submitted  to  Professor  F.  H. 
Pike  before  the  Commission,  together  with  the  answers  to 
them,  are  here  reported  verbatim. 

Dr.  Sachs  :  I  would  like  to  ask  Dr.  Pike  whether  the  movements 
of  that  dog  resembled  in  any  way  such  movements  as  we  have 
described  here  as  following  encephalitis?  Were  they  of  the  chore- 
atic or  myoclonic  type? 

Dr.  Pike:  I  think  from  the  description  I  have  heard,  and  from 
some  cases  I  have  seen,  they  are  very  much  like  those.  They  are 
very  general;  they  involve  even  the  jaw  muscles.  You  could  hear 
the  teeth  click.  And  there  was  some  respiratory  change.  At  times 
the  breath  would  come  in  gasps.  At  first  there  was  some  weakness 
of  the  muscles  of  the  limbs.  The  dog  was  unable  to  go  up  or  down 
stairs  unassisted,  but  that  passed  off  in  time.  The  dog  became  able 
to  draw  a  sled  with  two  boys  on  it.  I  couldn't  notice  any  difference 
in  the  general  intelligence  or  general  habits. 

Dr.  Barker:  Dr.  Hohman  mentioned  a  case  in  which  there 
was  rhythmical  myoclonia.  The  rate  of  the  myoclonic  contractions 
was  in  a  definite  ratio  with  the  respiratory  rate.  I  think  he  referred 
to  some  work  of  Dr.  Pike's  suggesting  that  this  meant  that 
rhythmical  myoclonia  must  have  an  origin  in  the  medulla  oblon- 
gata. Can  you  give  us  any  data  on  that? 


240  ACUTE  EPIDEMIC  ENCEPHALITIS 

Dr.  Pike  :  It  is  only  in  cases  of  considerable  respiratory  difficulty 
that  I  have  observed  any  movements  outside  of  the  respiratory 
movements  under  experimental  conditions.  Many  of  these  symp- 
toms which  have  been  described,  seem  to  me  to  point  to  an  involve- 
ment of  the  medulla.  In  experimental  work  on  the  cerebellum  or 
any  region  around  the  fourth  ventricle  one  must  be  extremely 
cautious  to  avoid  pressure  or  irritation,  even  though  it  be  slight,  of 
the  floor  of  the  fourth  ventricle.  I  am  in  doubt  yet  sometimes  as 
to  the  actual  effects  of  cerebellar  lesions.  I  am  not  sure  that  they 
are  uncomplemented  by  effects  on  the  floor  of  the  fourth  ventricle. 
In  cases  of  increased  excitability  of  nerve  cells  which  one  might 
possibly  have  in  this  disease  of  encephalitis,  there  is  of  course  a 
possibility  that  some  of  these  muscular  movements  might  arise 
during  respiration  and  be  associated  with  respiratory  movements. 
I  don't  think  we  have  any  definite  proof. 

CONCLUSIONS    OF   THE    COMMISSION 

The  Commission  feels  that  the  evidence  submitted  before 
it  on  the  bacteriology  and  pathogenesis  of  epidemic  encepha- 
litis, together  with  the  incidental  additions  brought  out  in  the 
questionnaire,  while  not  entirely  conclusive  as  to  the  specific 
nature  of  epidemic  encephalitis  and  its  productive  organism, 
yet  is  of  the  greatest  weight.  The  work  of  Drs.  Loewe  and 
Strauss,  confirmed  by  Dr.  Thalhimer  and  by  many  European 
investigators,  notably  Levaditi  and  Harvier,  Mcintosh  and 
TurnbuII,  and  Ottolenghi,  D'Antona  and  Tonietti,  seems  to 
the  Commission  to  merit  high  commendation  as  having 
established  apparently  the  closest  relationship  between 
organism  and  disease.  The  negative  attitude  was  not  one 
which  pointed  out  errors  of  technique  or  fault  in  material 
or  error  in  conclusion,  but  only  inability  to  reproduce  the 
same  effect.  And  there  is,  it  seems  to  the  Commission,  room 
for  this  discrepancy  in  the  lack  of  using  material  obtained 
by  different  methods,  and  by  the  use  of  presumably  different 
filters.  The  commendable  attitude  of  the  investigators  in 
desiring  to  remove  their  differences  by  the  respective  use  of 
each  others'  material  and  technical  apparatus,  lends  hope 
that  unity  of  conclusion  will  soon  eventuate. 


BIBLIOGRAPHY 

Abrahamson,   I.   Prevalence  of  infectious  lethargic  encephalitis. 

N.  York  M.  J.,  19 1 9,  cix,  879. 
Abt,   I.  Acute  non-suppurative  encephalitis  in  children,  J.  Am. 

M.  Assn.,  1906,  xlvii,  1184-1188. 
Achard,  L.  E.  La  diversite  clinique  de  I'encephalite  Iethargique, 

Bull.  Acad,  de  med.,  Par.,  Feb.  2,  1920,  pp.  106-111. 
Alexander,  J.  B.  Cases  resembling  epidemic  encephalitis  occurring 

during  the  influenza  epidemic.  Brit.  M.  J.,  19 19,  i,  794-795. 
Alexander,  M.  E.,  and  Allen,    H.    E.   Lethargic   encephalitis: 

Report   of  cases   and   analysis    of  literature,    Arch.  Neurol. 

&  Psychiat.,  May,  1920,  p.  485. 
Alfred-Khoury.    Note    sur    un    cas    d'encephalite  Iethargique, 

Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,  1918,  xlii,  455-457- 
Allen,  W.   C.   Epidemic  encephalitis.   South.  M.  J.,    19 19,  xii, 

231-235. 
Arana,  F.  Lethargic  encephalitis  in  Guatemala.  J.  Am.  M.  Assn., 

1920,  Ixxiv,  66. 
Ardin-Delteil.    Un    cas    d'encephalite    Iethargique    observe    a 

Alger,  Bull,  et  mem.  Soc.  med.  d.  hop  dePar.,  191 8,  xlii,  577_58i- 
Ascoli,  V.   Sulla    cosidetta    encefalite    Ietargica,    Riforma  med., 

Napoli,  Roma,  1919,  xxxv,  945. 
Audibert,    V.    Encephalite    Iethargique.    Marseille    med.,  19 19, 

Ivi,  337-343. 

Babonneix,  et  al.  Lethargic  encephalitis.  Bull,  med.,  Par., 
1920,  xxxiv,  801,  828. 

Barber,  M.  C.  A  case  of  encephalitis  Iethargica.  Brit.  M.  J., 
1920,  i,  500. 

Barker,  L.  F.,  Cross,  E.  S.  and  Irwin,  S.  W.  Epidemic  acute  and 
subacute  nonsuppurative  inflammations  of  the  nervous  sys- 
tem prevalent  in  United  States  in  1918-1919:  Encepha- 
litis; encephalo-myclitis;  polyneuritis;  meningo-encephalo- 
myeloneuritis.  Am.  J.  M.  Sc,  1920,   clix,  157  and  337. 

Bartels  and  Furstner.   Meningomyclitis  diffusa  hemorrhagic-.-!. 
Arch.  J.  Psychiat.,  Bcri.,  1902. 
ie  241 


242  ACUTE  EPIDEMIC  ENCEPHALITIS 

Bashford,   E.   F.   The  experimental  reproduction   of  influenza, 

nephritis  and  encephalitis.  Brit.  M.  J.,  191 9,  i,  601-602. 
Bassoe,    P.    The   delirious   and   the   meningoradicular   types    of 

epidemic  encephalitis.  J.  Am.  M.  Assn.,   1920,  Ixxiv,   1009- 
1012. 
Bassoe,  P.,  and  Hassin,  G.  B.  A  contribution  to  the  histopath- 

ology  of  epidemic  lethargic   encephalitis.   Arch.   Neurol.    & 

Psychiat.,  19 19,  ii,  24-40. 
Batten,  F.  E.,  and  Still,  G.  F.  Epidemic  stupor  in  children. 

Lancet.  191 8,  i,  636. 
Beall,   K.   H.   Sleeping  sickness   (lethargic  encephalitis).    Texas 

State.  J.  M.,  1919-1920,  xv,  129. 
Belin,    H.    A    case    of   encephalitis  Iethargica  with  progressive 

paralysis.  Boston  M.  €f  S.  J.,  1919,  clxxx,  741. 
Benthin,  W.  Lethargic  encephalitis.  Zentralbl.  J.  Gyn'dk.,  Leipz., 

1920,  xliv,  673. 
Bergeron,  P.  N.  A  case  of  lethargic  encephalitis.  Arch.  Neurol.  €f 

Psychiat.,  1919,  ^,141-143. 
Bernhardt,    G.,    and   Simons,   A.    Zur   encephalitis   Iethargica. 

Neurol.  CentralbL,  Leipz.,  1919,  xxxviii,  705-715. 
Boccolari  and   Panini.   Bacteriology  of  epidemic  encephalitis. 

Rijorma  med.,   Napoli,   Roma.,    1920,  xxxvi,    126;  abstr.,  J. 

Am.  M.  Assn.,  1920,  Ixxiv,  1290. 
Bond,    E.   D.    Epidemic   encephalitis   and   catatonic   symptoms. 

Am.  J.  Insan.,  January,  1920,  p.  261. 
Bourges,  H.,  et  al.  Lethargic  encephalitis.  Bull,  et  mem.  Soc.  med. 

d.  hop.  de  Par.,  1920,  xliv,  842,  848,  881. 
Sequels  of  epidemic  encephalitis.  Bull,  et  mem.  Soc.    med.  d. 

hop.  de  Par.,  1920,  xliv,  995. 
Boveri,  P.  Myoclonic  form  of  epidemic  encephalitis.  Brit.  M.  J., 

1920,  i,  570. 
Spinal  fluid  in  epidemic  encephalitis.  Bull,  et  mem.  Soc.  med.  d. 

hop.  de  Par.  1920,  xliv,  960. 
Boyd,  W.  Winnipeg  epidemic    of  lethargic  encephalitis.   Canad. 

M.  Ass.  J.,  1920,  x,  117. 
Bradford,  J.  R.,  A  communication  on  a  "filter-passing"  virus  in 

certain  diseases,  with  special,  reference  to  polyneuritis,   en- 
cephalitis,   trench   fever,    influenza   and   nephritis.    Brit.  M. 

J.,  19 1 9,  i,  599-600. 
Bradford,  J.  R.  Bashford,  E.  F.,  and  Wilson,  J.  A.  Acute  in- 


BIBLIOGRAPHY  243 

fective    polyneuritis.    Quart.    J.    Med.,    Oxford,    19 18-19 19, 

xii,  88-126. 
Brasher,  C.  W.,  Caldwell,  J.  R.,  and  Coombe,  E.  J.  A  report  on 

two  cases  of  encephalitis  Iethargica.  Brit.  M.  J.,  19 19,  i,  733. 
Breinl,  A.  Clinical,  pathological  and  experimental  observations 

on  the  mysterious  disease:  A  clinically  aberrant  form  of  acute 

poliomyelitis.  Med.  J.  Australia,  Sydney,  March  16,  191 8. 
Brown,  P.  K.  Notes  on  encephalitis  Iethargica  in  San  Francisco. 

Calif.  State  J.  M.,  19 19,  xvii,  427-429. 
Bucklers.  Zur  Kenntniss  der  acuten  primaren  hamorrhagischen 

Encephalitis.  Arch.  j.  Psychiat.,  Berl.  1892,  xxiv,  730-757. 
Burger,  H.  Un  cas  d'encephalite  Iethargique.  Arch,  d'opht.,  Par., 

19 1 8,  xxx vi,  356-362. 
Burger,  H.,  and  Focquet,  R.  L'encephalite  Iethargique.  Arch. 

med.  beiges,  Brux.,  1919,  Ixxii,  19-25. 
Burrowes,   M.   T.   Neuritis  of  the  cranial   nerves  in  lethargic 

encephalitis  and  the  differential  anatomic  diagnosis  between 

it    and    acute   poliomyelitis.    Arch.    Int.    Med.,     1920,    xxvi, 

477-509. 
Buzzard,  E.  F.  Encephalitis  Iethargica.  Proc.  Roy.  Soc<  Med.,  Lond., 

1918-1919,  xii  (2),  Sect.  Neurol.,  56-64. 
Acute  epidemic  encephalitis.  Lancet.  191 8,  i,  715. 
Lethargic  encephalitis.  Lancet,  191 8,  ii,  835-837. 
Buzzard,  E.  F.,  and  Greenfield,  J.  G.  Lethargic  encephalitis; 

sequels  and  morbid  anatomy.  Brain,  Lond.,  1920,  xlii,  305. 
Cadwalader,  W.  B.  Occurrence  of  bilateral  sympathetic  ophthal- 
moplegia: Its  significance  in  lethargic  encephalitis.  J.  Am. 

M.  Assn.,  1920,  Ixxiv,  13 15. 
Calhoun,  H.  A.  Histopathology  of  the  brain  and  spinal  cord  in  a 

case    presenting    a    post-influenzal    encephalitis    syndrome. 

Arch.  Neurol.  &  Psychiat.,  1920,  iii,  1. 
Camac,  J.  A  case  of  encephalitis:  lethargy  and  myoclonus.  Brit. 

M.  J.,  1920,  i,  704. 
Campbell,  W.  A.  Lethargic  encephalitis.  Med.  Rec.  1920,  xcviii,  434. 
Center,   C.   D.   Acute  hemorrhagic  encephalitis.  Phila.    M.  J., 

1900,  vi,  955-957- 
Chalmers,  A.   K.  On  some  unusual  forms  of    nervous  disease. 

Glasgow  M.  J .,  191 8,  xc,  79-81. 
Chambers,  E.  R.  A  sporadic  case  of  encephalitis  Iethargica.  Brit. 

M.  J.,  mjkj,  ii,  528. 


244  ACUTE  EPIDEMIC  ENCEPHALITIS 

Chartier,  M.  L'encephalite  aigue  non  suppuree.  These  de  Paris, 

1907. 
A  propos  de  I'encephalite  Iethargique.  Presse  med.,  191 8,  xxvi, 

660. 
Chauffard,  A.  L'encephalite  Iethargique.  Rev.   gen.   de  din.  et 

de  therap.,  Par.,  19 18,  xxxii,  577-579. 
Chauffard,  A.,  and  Bernard,  (Mile.)  M.  Encephalite  Iethargi- 
que. Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,  19 18,  xlii,  330-336. 
Deux  cas  d'encephalite  Iethargique.  Bull,  et  mem.  Soc.  med.  d. 

hop.  de  Par.,  19 18,  xlii,  470-475. 
Church,  A.  Polioencephalitis  superior  in  a  man  thirty-one  years 

of  age.  J.  Nerv.  &  Ment.  Dis.,  1901,  xxviii,  303-305. 
Claisse,  P.  Encephalite  Iethargique.  Bull,  et  mem.  Soc.  med.  d. 

hop.  de  Par.,  1919,  xliii,  22-225. 
Claude,  H.  Apropos  de  I'encephalite  Iethargique.  Bull,  et  mem. 

Soc.  med.  d.  hop.  de  Par.,  191 8,  xlii,  364-368. 
Claude,    H.,    and    Schaeffer,    H.    Encephalite   Iethargique    a 

forme  aigue  avec  examen  anatomique.   Bull,   et  mem.   Soc. 

med.  d.  hop.  de  Par.  191 8,  xlii,  521-526. 
Cleland,  J.  B.,  and  Campbell,  A.  W.  Australian  epidemic  of 

acute  encephalomyelitis.  J.  Nerv.  &  Ment.  Dis.,  February, 

1920,  p.  137. 
The  nature  of  the  recent  Australian  epidemics  of  acute  encepha- 
lomyelitis; successful  conveyance  of  virus  to  sheep,  a  calf, 

and  a  horse.  Med.  J.  Australia,  Sydney,  19 19,  i,  234-236. 
Climenko,  H.  Lethargic  encephalitis,  forme  fruste.  N.  York  M. 

J.,  1919,  cix. 
Cohn,  W.,  and  Lauber,  I.  Epidemic  encephalitis.  MiXnchen.  med. 

Wchnschr.,  1920,  Ixvii,  688. 
Comby,  J.  Acute  encephalitis  in  children.  Bull,  el  mem.  Soc.  med. 

d.  hop.  de  Par.,  Feb.  6,  1920,  p.  161;  abstr.,  J.  Am.  M.  Assn., 

1920,  Ixxiv,  1489. 
Encephalite   Iethargique.    Arch.    d.    med.    d.    enj.,    Par.,    19 19, 

xxii,  25^-265. 
Cords,  R.  Eye  symptoms  in  lethargic  encephalitis.  Munchen.  med. 

Wchnschr.,  1920,  Ixvii,  62J. 
Courcoux  et  al. :  Lethargic  encephalitis.  Bull,  et  mem.  Soc.  med.  d. 

hop.  de  Par.,  1920,  pp.  223,  230,  232,  237,  244,  260,  262. 
Cramer,  A.  Au  sujet  de  I'encephalite  Iethargique.  Rev.  med.  de 

la  Suisse  Rom.,  Geneve,  1919,  xxxix,  197-21 1. 


BIBLIOGRAPHY  245 

Creyx:  Quelques  remarques  sur  I'encephalite  aigue  non  suppuree. 

J.  de  med.  de  Bordeaux,  191 8,  xlviii,  62-67. 
Crofton,  W.  M.  Association  of  lethargy  with  influenza  bacillus. 
Brit.  M.  J.,  1920,  i,  431. 
History  of  epidemic  encephalomyelitis.   Boston  M.   &  S.   J., 
1920,  clxxxii,  34. 
Crookshank,  F.  G.  Botulism?  Lancet,  1918,  i,  653-654. 

Botulism  and  Heine-Medin  Disease.  Lancet,  191 8,  i,  699-702. 
Epidemic  encephalomyelitis  and  influenza.  Lancet,  1919,  i,  79- 
Cruchet,   R.  Bordeaux  conception  of  lethargic  encephalitis.  N. 
York  M.  J.,  Aug.  7,  1920,  p.  173. 
Diffuse  encephalomyelitis  and  lethargic  encephalitis.  Paris  med., 

1919,  ix,  474. 

Cruchet,   R.,  Verger  and  Davezac.   Encephalite  Iethargique. 

J.  de  med.  de  Bordeaux,  xlix,  119. 
Cumston,  C.  G.  Clinical  notes  from  France.  Sleeping  sickness.  N. 

York  M.  J.,  ex,  550,  720. 
Lethargic    encephalitis    in    France    and    Switzerland.    N.  York 

M.  J.,  Aug.  7,  1920,  p.  185. 
DaFano,   C,  and  Ingleby,   H.   Demonstration  of  preparations 

from  cases  of  encephalitis  Iethargica.  Proc.  Roy.  Soc.  Med., 

Lond.,  1918-1919,  xii  (3),  Sect,  of  Pathol.,  pp.  42-45. 
Dana,  C.  L.  The  nonsuppurative  inflammations  of  the  brain,  with 

a  report  of  a  case  of  hemorrhagic  (malarial?)   encephalitis. 

Med.  Rec,  1900,  Iviii,  1-6. 
Demole,  V.  Lethargic  encephalitis.  Rev.  med.  de  la  Suisse  Rom., 

Geneve,  1920,  xl,  352,  353. 
Denechau,    D.   Lethargic   encephalitis.   Bull,   med.,    Par.,    1920, 

xxxiv,  69;  abstr.,  J.  Am.  M.  Assn.,  1920,  Ixxiv,  831. 
Dexler,  H.  Beitrage  zur  comparitiven  pathologischen  Anatomie 

der  akuten  Encephalitis.  Monatschr.  j.  Psychiat.  u.  Neurol, 

Berl.,  1903,  xiii,  97,  210. 
Diagnosis  of  Lethargic  Encephalitis,  special  article.  Brit.  M.  J., 

1920,  i,  409. 

Dimitz,  L.  Epidemic  choreiform  encephalitis.  Wien.  klin.  Wchnschr., 

1920,  xxxiii,  163. 
Dodson,  L.  Botulism.  Lancet,  1918,  i,  615. 
Dopter  and  Oberthur.  Encephalite  aigue  experimentale.  Compt. 

rend.  Soc.  de  bioi,  Par.,  1907,  Ixii,  848. 
Dopter,    C.    Hyperglycorachia    in    epidemic    encephalitis.    Bull. 


246  ACUTE  EPIDEMIC  ENCEPHALITIS 

Acad,  de  med.,  Par.,  1920,  Ixxxiii,  203;  abstr.,  J.  Am.  M.  Assn., 

1920,  Ixxiv,  1545. 
Draper,  G.  Report  of  an  inquiry  into  an  obscure  disease,  en- 
cephalitis Iethargica.  Report  Local  Govt.  Board  on  Pub.  Health 

and  Med.  Subjects,  n.  s.,  No.  121,  London,  1918. 
Dundas,  G.  H.  G.  A  case  of  lethargy.  Lancet,  1919,  ii,  435. 
Dunn,  J.  F.  Sleeping  sickness.  Kentucky  M.  J.,  1920,  xviii,  300. 
Eaddy,   J.   G.  Lethargic  encephalitis.  J.   South  Car.  M.  Assn., 

19 19,  xv,  500-502. 
Eagleton,  W.  P.  Encephalitis  Iethargica.  Ann.  Otol.,  Rhinol.  & 

Laryngol,  19 19,  xxxviii,  940-944. 
Ebstein.    Einige   Bemerkungen    iiber   die   sogennante    "Nona." 

Berl.  klin.  Wchnschr.,  1891,  No.  41. 
Economo,  C.  von.  Chronic  lethargic  encephalitis.  Miinchen.  med. 

Wchnschr.,    19 19,  p.    131 1 ;  abstr.,  J.  Am.  M.  Assn.,    1920, 

Ixxiv,  989. 
Epidemiology  of  lethargic  encephalitis.  Schweiz.  Arch.  j.  Neurol. 

u.  Psychiat.,  1920,  vi,  276. 
Encephalitis  Iethargica.  Wien.  klin.  Wchnschr.,  191 7,  xxx,  581- 

Ely,  F.  A.  Lethargic  encephalitis;  preliminary  report.  J.  Am.  M. 

Assn.,  1919,  Ixxii,  985. 
Encephalitis  Iethargica.  A  new  disease?  special  article.  J.  Am.  M. 

Assn.,  19 1 9,  Ixxii,  414. 
Epidemic   or   lethargic   encephalitis    (Nona),    special   article.    J. 

Am.  M.  Assn.,  1919,  Ixxiii,  794. 
Etienne,  G.  Encephalite  Iethargique.  Bull.  et.  mem.  Soc.  med.  d. 

hop.  de  Paris,  1919,  xliii,  482-484. 
Fairbanks,  A.  W.  Encephalitis  Iethargica.  Boston  M.  &  S.  J., 

1919,  clxxxi,  578-582. 
Findlay,   L.   Lethargic   encephalitis.   Glasgow  M.   J.,     19 18,   xl, 

193, -204. 
Flatau.  Uber  acute  entziindliche  Prozesse  in  Gehirn.  Kongress- 

Berichte  Poln.  Aertze,  Krakau,  1900. 
Flexner,  S.  Lethargic  encephalitis,  etc.  J.  Am.  M.  Assn.,  1920, 

Ixxiv,  865-869. 
Friedman,  E.  D.  Epidemic  encephalitis.  Med.  Rec,  1920,  xcviii, 

226. 
Friedmann,  M.  Studien  zur  pathologischen  Anatomie  der  akuten 

Encephalitis.  Arch.  j.  Psychiat.,  Berl.,  1890,  xxi,  461. 


BIBLIOGRAPHY  247 

Zur  Lehre  insbesondere  zur  pathologischen  Anatomie  der  nicht 
eitrigen  Encephalitis.  Deutsch  Zlschr.f.  Nervenh.,  Leipz.,  1898, 

xiv,  937143- 
Encephalitis  und  Hirnabscess.    Handbuch   der   pathologischen 

Anatomie  der  Nervensystems.  Berlin,  1904,  i,  468-494. 
Garnett,  A.  Y.  P.  Lethargic  encephalitis  as  a  complication  of 

pregnancy  and  labor.  J.  Am.  M.  Assn.,  1920,  Ixxiv,  13 15. 
Garrahan,  J.  P.  Encefalitis  aguda  en  una  nifia  de  dos  afios  y 

medio;   curacion   rapida  y  completa.   Semana  med.,   Buenos 

Aires,  191 8,  xxv,  665-668. 
Gerstmann,  J.  Clinical  types  of  encephalitis.  Wien.  klin.  Wchnschr., 

1920,  xxxiii,  165. 
Gordon,  A.   Encephalitis  Iethargica.  N.   York  M.  J.,   19 19,  cix, 

837- 
Goudie,  A.  S.  A  case  of  encephalitis  Iethargica.  Brit.  M.  J.,  1920, 

i,  671. 
Grace,  E.  J.  Lethargic  encephalitis.  Report  of  a  suggestive  case. 

Long  Island  Med.  J.,  19 19,  xiii,  391-394. 
Grahe,  K.  The  internal  ear  in  lethargic  encephalitis.  Miinchen. 

med.  Wcbnschr.,  1920,  Ixvii,  629. 
Groebbels,  F.  Lethargic  encephalitis.  Miinchen.  med.  Wchnschr., 

1920,  Ixvii,  131. 
Guerin,  A.  Un  cas  d'encephalite  Iethargique.  Rev.  gen.  de  din.  el 

de  therap.,  Par.,  19 19,  xxxiii,  583. 
Hala,  W.  W.,  and  Smith,  C.  M.  Case  of  meningo-encephalitis 

(lethargic    encephalitis).    Arch.    Neurol.    &   Psychiat.,    1920, 

iii,  160. 
Halbron,  P.  L'encephalite  Iethargique.  Med.  jrang.,  Par.,  1919,  i, 

155-157. 
Hall,  A.  J.  Botulism.  Lancet,  1918,  i,  568. 

Epidemic  encephalitis.  Brit.  M.  J.,  19 18,  ii,  461. 
Hamill,  R.  C.  Four  cases  of  encephalitis  with  involuntary  move- 
ments. Arch.  Neurol.  &  Psychiat.,  1920,  iv,  44. 
Hammes,   E.  M.,  and  McKinley,  J.  C.  Lethargic  encephalitis; 

symptomatology     and     histopathology.     Arch.     Int.     Med., 

1920,  xxvi,  60. 
Harris,  W.  Botulism,  Lancet,  1918,  i,  568. 

The  nervous  system  in  influenza.  Practitioner,  Lond.,  1919,  cii, 

89-100. 
Harvier,  P.,  et  al.  Epidemic  encephalitis.  Bull,  et  mem.  Soc.  med. 


248  ACUTE  EPIDEMIC  ENCEPHALITIS 

d.  hop.  de  Par.,  1920,  xliv,  179;  abstr.,  J.  Am.  M.  Assn.,  1920, 

Ixxiv,  1489. 
Hassin,  G.  B.  Acute  encephalitis.  Med.  Rec,  1909,  Ixxv,  223-227. 
Hayem,   G.   Etude  sur  Ies  diverse  formes  d'encephalite.    These 

de  Paris,  1868. 
Heiman,  H.  Postinfluenzal  encephalitis.  Am.  J.  Dis.  Child.,  19 19, 

xviii,  83-87. 
Hershberg,  H.  Lethargic  encephalitis,  report  on  a  case.  N.  York 

M.  J.,  1919,  ex,  899-900. 
Hershfield,  A.  S.  Epidemic  encephalitis  in  Chicago.  An  analysis. 

Illinois  M.  J.,  1919,  xxxvi,  27-29. 
Hesnard.     Mental    disturbances    with    epidemic    encephalitis. 

Encephale,  Par.,  1920,  xv,  443. 
Hoestermann.  The  epidemic  appearance  of  encephalitis.  Deulsch. 

med.  Wchnschr.,  1920,  xlvi,  707. 
Hoffmann,  R.  V.  Epidemic  encephalitis  in  northern  Indiana.  J. 

Indiana  M.  Assn.,  1920,  xiii,  228. 
Hoke,  E.  Polyuria  with  epidemic  encephalitis.  Wien.  klin.  Wchn- 
schr., 1920,  xxxiii,  652. 
Holden,  W.  A.,  and  Collins,  J.  Polio-encephalitis  superior;  its 

causation,   clinical  course  and  termination;  with  report  of 

six  cases.  J.  Am.  M.  Assn.,  1908,  514-518. 
House,  S.  J.  Observations  on  a  green-producing  coccus  from  the 

brain  in  a  case  of  encephalitis.  J.  Am.  M.  Assn.,  1920,  Ixxiv, 

884-885. 
House,  W.  E.  (Lethargic)  encephalitis.  Clinical  review  of  cases  in 

the  Pacific  Northwest.  J.  Am.  M.  Assn.,  1920,  Ixxiv,  372. 
Howe,  H.  S.  The  thalamic  syndrome  in  epidemic  encephalitis. 

Neurol.  Bull,  19 19,  ii,  190. 
Hunt,  E.  L.  Encephalitis  Iethargica.  N.  York  State  J.  M.,  1920, 

xx,  137. 
James,  S.  P.  Lethargic  encephalitis;  note  on  its  distribution  in 

England.  Lancet,  19 18,  ii,  837. 
Jeanselme,  E.  Lethargic  encephalitis  in  a  syphilitic.  Semana  med., 

Buenos  Aires,  1920,  xxvii,  609;  abstr.,  J.  Am.  M.  Assn.,  1920, 
^  Ixxv,  774. 
Syphilis  and  epidemic  encephalitis.  Bull.  Acad,  de  med.,  Par. 

1920,  Ixxxiii,  210;  abstr.,  J.  Am.  M.  Assn.,  1920.,  Ixxiv,  1545. 
Jendrassik  and  Marie,  P.  Contribution  a  P etude  de  I'hemia- 

trophie  cerebrale  par  sclerose  Iobaire.  Arch,  de  physiol.  norm. 

et  path.,  Par.,  1885. 


BIBLIOGRAPHY  249 

Kennedy,  F.  Epidemic  encephalitis  with  stupor.  Med.  Rec,  19 19, 

xcv,  631-633. 
Khonay,  A.  Notes  sur  un  cas  d'encephalite  Iethargique.  Bull,  et 

mem.  Soc.  med.  d.  hop.  de  Par.,  May  17,  19 18. 
Klieneberger,  C.  Influenzal  and  lethargic  encephalitis.  Deutsch 

med.  Wchnschr.,  Berl.  &  Leipz.,  1920,  xlvi,  654. 
Koch,  G.  W.  Encephalitis  Iethargica.  J.  Iowa  State  M.  Soc.,  19 19, 

ix,  333-337-  ..... 

Kramer  and  Henneberg.  Uber  disseminierte  Encephalitis.  Berl. 

klin.  Wchnschr.,  1917,  Iiv,  219. 
Labbe,  M.,  et  al.  Lethargic  encephalitis.  Bull,  et  mem.  Soc.  med.  d. 

hop.  de  Par.,   1920,  xliv,   194,   198,   199,  207,  209;  abstr.,  J. 

Am.  M.  Assn.,  1920,  Ixxiv,  1546. 
de  Lapersonne,  F.  Ocular  manifestations  of  lethargic  encephalitis. 

Presse  med.,  Par.,  1920,  xxviii,  493. 
Latreille,  E.  La  maladie  du  sommeil.  Quelques  notes  de  pratique 

sur  la  semiologie,  son  involution  clinique  et  son  substratum 

anatomique   etayees   de  quatre   observations   cliniques   per- 

sonelles,   dont  une  avec  autopsie.    Union  med.   du  Canada, 

Montreal,  1920,  xlix,  57-63. 
Laubie.  Encephalite  Iethargique.  Bull.  Acad,  med.,  Paris,   1920, 

Ixxxiii,  246;  abstr.,  J.  Am.  M.  Assn.,  1920,  Ixxiv,  1545. 
Leichenstern.  Mitteilungen  iiber  die  influenza  epidemie  in  Coin. 

Deutsch  med.  Wchnschr.,  Berl.  &  Leipz.,  1890,  p.  510. 
Uber  primare  akute  hamorrhagische  Encephalitis.  Deutsch  med. 

Wchnschr.,  Berl.  &  Leipz.,  1892,  pp.  39-40. 
Die   Influenza,    Spec.    Pathol,    u.   Therap.  (Nothnagel).  Wien, 

1896,  Bd.  4. 
Leiner,  J.  H.  Lethargic  encephalitis;  clinical  aspects.  N.  York  M. 

J.,  Aug.  7,  1920,  p.  178. 
Lereboullet,  P.,  and  Hutinel,  J.  Un  nouveau  cas  d'encephalite 

Iethargique,   Bull,  et  mem.  Soc.   med.  d.   hop  de  Par.,    1919, 

xliii,  302-304. 
Leri,  A.,  and  Gay,  R.  Spastic  paraplegia  left  by  epidemic  encepha- 
litis. Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,  1920,  xliv,  876. 
Lesne"  et  al.  Encephalite  Iethargique.  Bull,  et  mem.  Soc.  med.  d. 

bdp.  de  Par.,  1920,  xliv,  756,  769,  784. 
Lethargic   encephalitis:   A    notifiable   disease    in    England.    Pub. 

Health  HepL,  Wash.,  191 9,  xxxiv,  314-318. 
Levaditi,  C.,  and  Harvier,   P.  Virus  of  epidemic  encephalitis. 

Bull.  Acad,  de  med.,  Par.,  1920,  p.  365. 


25o  ACUTE  EPIDEMIC  ENCEPHALITIS 

Levy,  P.  P.  Three  cases  of  epidemic  encephalitis  in  one  family. 
Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,  1920,  xliv,  1007. 

Lhermitte,  J.  L'encephalite  Iethargique.  Ann.  de  med.,  Par., 
1919,  vi,  306-336. 

Licen,  E.  Uber  nichteitrige  hamorrhagische  encephalitis.  Ztschr. 
j.  d.  ges.  Neurol,  u.  Psychiat.,  Berl.  &  Leipz.,  191 8,  xlii,  1-20. 

Loeser.  Cases  of  polio-encephalitis.  Med.  J.  S.  Africa,  Johannesb., 
1918-1919,  xiv,  406-408. 

Loewe,  L.,  Hirshfeld,  S.,  and  Strauss,  I.  Studies  in  epidemic 
encephalitis  (encephalitis  Iethargica).  J.  Inject.  Dis.,  1919, 
xxv,  378-383. 

Loewe,  L.,  and  Strauss,  I.  The  diagnosis  of  epidemic  encephalitis. 
J.  Am.  M.  Assn.,  1920,  Ixxiv,  1373. 

Loewenthal,  W.  Bacteriologic  findings  in  lethargic  encephalitis. 
Deutsch  med.  Wchnschr.,  Berl.  &  Leipz.,  1920,  xlvi,  289. 

Longuet,  P.  La  nona.  Semaine  med.,  Par.,  1892,  xii,  275-278. 

Lortat-Jacob  and  Haelez,  G.  L.  Un  cas  d'encephalite  Iethargique; 
guerison;  valeur  et  evaluation  des  signes  oculaires.  Bull,  et 
mem.  Soc.  med.  d.  hop  de  Par.,  19 18,  xlii,  439-444. 

Low,  G.  G,  and  Mott,  F.  W.  Examination  of  the  tissues  of  a  case 
of  sleeping  sickness  in  a  European.  Brit.  M.  J.,  1889,  i>  1666. 

Lowe,  F.  Two  cases  of  polio-encephalitis.  Guy's  Hosp.  Gaz., 
London,  191 8,  xxxii,  22^-22^. 

Loygue,  M.  G.  Sur  un  cas  de  meningo-encephalite  tuberculeuse. 
Remarques  a  propos  de  l'encephalite  Iethargique.  Bull,  et 
mem.  Soc.  med.  d.  hop.  de  Par.,  1919,  xliii,  769-775. 

MacNalty,  A.  S.  Report  of  an  inquiry  into  an  obscure  disease, 
encephalitis  Iethargica.  Rept.  Local  Govt.  Board  on  Pub.  Health 
and  Med.  Subjects,  n.  s.,  No.  121,  London,  191 8,  pp.  12,  69; 
also  Proc.  Royal  Soc.  Med.,  London,  19 18,  xii  (1),  Sect.  Med., 
i-xxiii. 

McAlpine,  D.  Case  of  myoclonic  form  of  acute  epidemic  encepha- 
litis. Lancet,  1920,  ii,  353. 

McDonald,  J.  A.  A  case  of  encephalitis  Iethargica.  Arch.  Neurol. 
&  Psychiat.,  1919,  ii,  134. 

McIntosh,  J.  Report  of  an  inquiry  into  an  obscure  disease,  en- 
cephalitis Iethargica.  Rept.  Local  Govt.  Board  on  Pub.  Health 
and  Med.  Subjects,  n.  s.,  No.  121,  London,  19 18,  p.  58. 

McIntosh,  J.,  and  Turnbull,  H.  M.  Experimental  transmission 
of  lethargic  encephalitis  to  a  monkey.  Brit.  J.  Exper.  Pathol., 
Lond.,  1920,  i,  89. 


BIBLIOGRAPHY  251 

Maggiora  et  al.  Bacteriology  of  epidemic  encephalitis.  Riforma 

med.,  Napoli,  Roma,  1920,  xxxvi,  1 14,  abstr.  J.  Am.  M.  Assn., 

1920,  Ixxiv,  1290. 
Maier,   H.  W.   Epidemic  encephalitis  at  Zurich.   Schweiz.  med. 

Wchnschr.,  1920,  1,  249. 
Marie,   P.  Lethargic  encephalitis   (Foreign  Correspondence).  J. 

Am.  M.  Assn.,  1920,  Ixxiv,  748. 
Marie,  P.,  and  Tretiakoff,  C.  Examen  histologique  des  centres 

nerveuxdans    deux    cas    d'encephalite    Iethargique.    Bull,  et 

mem.  Soc.  med.  d.  hop.  de  Par.,  19 18,  xlii,  475-479. 
Marie,  P.,  and  Mestrezat.  Lethargic  encephalitis.  Bull.  Acad,  de 

med.,  Par.,  1920,  Ixxxiii,  103. 
Marie,  P.,  and  Levy,  G.  The  Parkinson  syndrome  in  lethargic 

encephalitis.  Bull.  Acad,  de  med.,  Par.,  1920,  Ixxxiii,  539. 
Motor  disturbances  after  influenza  and  epidemic  encephalitis. 

Med.  Jrang.,  Par.,  1920,  i,  270;  abstr.,  J.  Am.  M.  Assn.,  1920, 

Ixxiv,  1288. 
Marie,  P.,  et  al.  Epidemic  encephalitis.  Bull,  et  mem.  Soc.  med.  de 

hop.  de  Par.,  1920,  xliv,  661,  668,  685,  689. 
Marinesco,   G.    Encephalite  Iethargique.   Bull.   Acad,   de   med., 

Par.,  1920,  Ixxxiii,  248. 
Pathologic  histology  of  epidemic  lethargic  encephalitis.   Bull. 

Acad,  de  med.,  Par.,  191 8,  Ixxx,  411. 
Report   of  an   inquiry   into   an   obscure   disease,    encephalitis 

Iethargica.  Rept.  Local  Govt.  Board  on  Pub.  Health  and  Med. 

Subjects,  n.  s.,  No.  121,  London,  1918,  p.  48. 
Marshall,  J.  N.  A  sporadic  case  of  polio-encephalitis.  Brit.  M. 

J.,  19 1 8,  ii,  8. 
Mathewson,  T.  H.  R.,  and  Latham,  O.  Acute  encephalitis  of 

unknown  origin.  M.  J.  Australia,  Sydney,  19 17,  ii,  352-357. 
Maurice,  P.  Les  formes  curables  des  meningitis  aigue  avec  Iymph- 

ocytose  rachidienne.  Paris  med.,  19 18,  xxix,  326-330. 
Mauthner,  L.  Zur  Pathologie  und  Physiologie  des  Schlafes  nebst 

Bemerkungen  iiber  die  "Nona."  Wien.  med.  Wchnschr.,  1890, 

xl,  961. 
Mayer,   W.   D.  Lethargic  encephalitis;  symptoms  and  physical 

signs.  Michigan  State  M.  J.,  1920,  xix,  360. 
Melland,  C.  H.  Epidemic  polio-encephalitis.  Brit.  M.  J.,  19 18,  i, 

559- 
Milian,  M.  G.  Grippe  et  encephalite  Iethargique.  Bull,  et  mem. 
Soc.  med.  d.  hop.  de  Paris,  191 9,  xliii,  225-228. 


252  ACUTE  EPIDEMIC  ENCEPHALITIS 

Miller,  J.  L.  Encephalomyelitis  disseminata  acuta.  J.  Am.  M. 
Assn.,  1903,  p.  1015. 

Mills,  C.  K.  Circumscribed  hemorrhagic  cortical  encephalitis, 
with  the  report  of  a  case  in  which  the  lesion  was  limited  to  the 
motor  zone,  the  chief  clinical  manifestation  Jacksonian 
epilepsy.  Rev.  Neurol.  &  Psychiat.,  Edinb.,  1907,  v,  89-97. 

Mills,  C.  K.,  and  Wilson,  G.  T.  Cerebellobulbar  polio-encephali- 
tis originating  during  or  after  epidemics  of  influenza  and  of 
poliomyelitis,  including  the  record  of  epidemic  encephalitis 
of  the  lethargic  type.  Arch.  Neurol,  df  Psychiat.,  i,  567-578. 

Morax,  V.  The  ocular  complications  of  lethargic  encephalitis. 
Brit.  J.  Ophth.,  1918,  ii,  529-533. 

Moritz,  F.  Epidemic  (lethargic)  encephalitis.  Munchen.  med. 
Wchnschr.,  1920,  Ixvii,  711. 

Morquio,  L.  Sobre  la  encephalitis  Ietargica.  Rev.  med.  del  Uruguay, 
Montevideo,  191 8,  xxi,  463-477. 

Morse,  P.  F.,  and  Crump,  E.  S.  Bacteriology  and  pathology  in  six 
cases  of  lethargic  encephalitis.  J.  Lab.  ~&  Clin.  M.,  1920,  p. 
275. 

Mott,  F.  W.  Discussion  of  encephalitis  Iethargica.  Lancet,  19 18, 
ii,  590. 
Histological  observations  on  sleeping  sickness  and  other  trypano- 
some  infections.  Seventh  report  of  the  Sleeping  Sickness  Com- 
mission of  the  Royal  Society,  1907;  also  Arch.  Neurol.  Path. 
Lab.  Lond.  County  Asyl.,  Claybury,  Lond.,  iii. 

Muller-Bergalonne,  G.  Lethargic  encephalitis  in  Switzerland, 
Abstr.  J.  Am.  M.  Assn.,  1920,  Ixxiv,  142. 

Muratow,  Klinische  und  anatomische  Beitrage  zur  Lehre  von 
den  primaren,  nicht  eitrigen  Encephalitis.  Monatschr.  j. 
Psychiat.  u.  Neurol,  BerL,  1902. 

Nauwerk.  Influenza  and  encephalitis.  Deutsch.  med.  Wchnschr., 
BerL  &Leipz.,  1895. 

Neal,  J.  B.  Meningeal  conditions  noted  during  epidemic  of  in- 
fluenza. J.  Am.  M.  Assn.,  19 19,  Ixxii,  714. 
Encephalitis  Iethargica.   Month.  Bull.   Dep.   Health,   N.    York, 

1919,  ix,  69-71. 
Lethargic    encephalitis;    preliminary    report.     Internat.    Clin., 
1919,  ii,  184-198. 

Netter,  A.  Treatment  of  lethargic  encephalitis.  Bull.  Acad,  de  med., 
Par.,  1920,  Ixxxiii,  303;  abstr.,  J.  Am.  M.  Assn.,  Ixxiv,  1607. 


BIBLIOGRAPHY  253 

Existence  de  l'encephalite  Iethargique  en  Angleterre,  Bull,  el 

mem.  Soc.  med.  d.  hop.  de  Par.,  19 18,  xlii,  384. 
L'encephalite   Iethargique    epidemique.    Bull.    Acad,    de   med., 

Par.,  1918,  Ixxix,  337-347^ 
L'encephalite  Iethargique  epidemique.  Paris  med.,   19 18,  xxxix, 

81-86. 
L'encephalite  Iethargique.  Presse  med.,  Par.,  1920,  xxviii,  193. 
Recrudescence  of  lethargic  encephalitis.  Bull.  Acad,  de  med.,  Par., 

1920,  Ixxxiii,  45;  abstr.,  J.  Am.  M.  Assn.,  1920,  Ixxiv,  704,  748. 
Sur  quelques  cas  d'encephalite  Iethargique  observes  recemment 

a  Paris.  Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,   191 8,  xlii, 

307-3II- 
Netter,  A.,  and  Sainton,  P.  L'encephalite  Iethargique.  Presse 

med.,  Par.,  191 8,  xxvi,  487. 
Noel,  H.  L.  C.  Encephalitis  Iethargica  and  typhus.  Lancet.    19 19, 

i,  156. 
Nukada,  S.  Case  of  lethargic  encephalitis.  Japan  Med.   World, 

Tokyo,  1920,  x,  No.  34. 
O'Carroll,  J.,  and  Nesb itt,  G.  Some  recent  cases  of  encephalitis 

Iethargica.  Dublin  J.  Med.  Sc,  19 19,  cxlvii,  206-216. 
O'Connor,  C.  E.  Epidemic  encephalitis  with  general  pneumococcus 
infection   without   pulmonary   involvement.  Med.    Rec,   191 9, 

xcvi,  410-412. 
Oehmig,   O.   Encephalitis  epidemica  choreatica.  Munchen.  med. 

Wchnschr.,  1920,  Ixvii,  660. 
Oliver,  D.  Etude  clinique  de  deux  cas  d'encephalite  Iethargique. 

Marseille-med.,  1919,  Ivi,  554-560. 
Oppenheim,   H.,   and   Cassirer,   R.   Die   Encephalitis.   2  Aufl., 

Wien.,  1907. 
Osler,  W.  The  Cerebral  Palsies  of  Children.  Philadelphia,  1889. 
Osnato,  M.  A  contribution  to  the  symptomatology  of  epidemic 

encephalitis.  N.  York  State  J.  M.,  1920,  xx,  140. 
Papin,  Denechau,  D.,  and  Blanc,  C.  Quatre  cas  d'encephalite 

Iethargique  a  Angers.   Leur  modality  clinique,   Ieurs  suites 

apres  cinq,  mois  d'evolution.  Bull,  et  mem.  Soc.  med.  d.  hop. 

de  Paris,  1919,  xliii,  659-672. 
Pardee,  I.  H.  Acute  descending  radicular  type  of  epidemic  en- 
cephalitis. Arch.  Neurol.  (>f  Psychiat.,  1920,  iv,  24. 
Parrott,  H.  W.  Tuberculous  meningitis  and  lethargic  encephalitis. 

Lancet,  19 19,  i,  998. 


254  ACUTE  EPIDEMIC  ENCEPHALITIS 

Patrick,  H.  T.  A  case  of  so-called  polio-encephalitis.  J.  Nerv.  & 

Merit.  Dis.,  1897,  xxiv,  595-597. 
Picken,  R.  M.  F.  Polio-encephalitis  and  an  epidemic  disease  of 

obscure  origin.  Med.  Officer,  Lond.,  191 8,  xx,  37. 
Pisani,  S.,  and  Varisco,  A.  Filtrable  polymorphous  coccus  cul- 
tivated   from  cases   of  epidemic   encephalitis.   Riv.    crit.    di 

Clin.  Med.,  Firenze,  1920,  xxi,  217. 
Pothier,    O.   L.   Lethargic   encephalitis;   preliminary   report.   J. 

Am.  M.  Assn.,  1919,  Ixxii,  715. 
Pribram,    H.    Uber    encephalitis.   Deutsch.   Arch.  f.   klin.   med., 

19 1 8,  cxxv,  160-167. 
Putnam,  J.  J.  A  contribution  to  the  clinical  history  of  non-sup- 

purative  acute  (hemorrhagic)  encephalitis,  with  the  report  of 

a  case  following  an  attack  of  mumps.  J.  Nerv.  €f  Ment.  Dis., 

1897,  xxiv,  1-14. 
Raymond  and  Cestan.  L'encephalite  aigue  hemorrhagique.  Gaz. 

d.  hop.,  Par.,  1904. 
Raymond  and  Phillippe.  Encephalite  aigue  senile.  Rev.  neurol., 

Par.,  1901,  p.  161. 
Re,  G.  La  cosi  detta  encefalite  Ietargica  acuta  epidemica  con- 

siderata   come   una   manifestazione   nervosa   delP   influenza. 

Rijorma  med.,  Napoli,  Roma,  1919,  xxxv,  851-856. 
Reece,   R.   J.,   and   MacNalty,   A.   S.   Encephalitis  Iethargica. 

Annual  Rept.  Local  Govt.  Board,    1918-1919,  London,    19 19, 

66-76. 
Reich,  H.  Epidemic  encephalomyelitis.  Schweiz.  med.  Wchnschr., 

1920,  1,  207;  abstr.,  J.  Am.  M.  Assn.,  1920,  Ixxiv,  1289. 
Reilly,  T.  F.  Hitherto  undescribed  sign  in  diagnosis  of  lethargic 

encephalitis.  J.  Am.  M.  Assn.,  1920,  Ixxiv,  735. 
Reinhart,    A.    Uber    encephalitis    non    pufulenta     (Iethargica). 

Deutscb.  med.  Wchnschr.,  19 19,  xlv,  514-517. 
Remlinger.  L'encephalite  Iethargique  a.  Tanger.  Bull.  Acad,  de 

med.,  Paris,  1920,  Ixxxiii,  112-116. 
Repond,  A.  Un  cas  de  poliencephalite  Iethargique.  Rev.  med.  de 

la  Suisse  Rom.,  Geneve,  19 19,  xxxix,  249-251. 
de  Rezende,    C.    Botulinus  poisoning  or  lethargic  encephalitis. 

Brazil-Med.,  Rio  de  Jan.,  1920,  xxxiv,  351. 
Rice-Oxley,  A.  J.  A  case  of  epidemic  encephalitis.  Lancet.,   19 18, 

ii,  15- 
Riggs,  C.  E.  Epidemic  lethargic  encephalitis,  Minnesota  Med.} 
1920,  iii,  49-53. 


BIBLIOGRAPHY  255 

Rivas,  Jordan  R.  Sobre  uncaso  de  encefalitis  Ietargica.  Semana 

med.,  Buenos  Aires,  1919,  xxvi,  Part  2,  p.  483. 
Robinson,  C.  A.  Lethargic  encephalitis.  Indianapolis  M.  J.,  19 19, 

xxii,  163. 
Roger,  H.  Classification  of  epidemic  encephalitis.  Progres  med., 

Par.,  1920,  xxxv,  247. 
Rossi,  I.  Coincidence  chez  Ies  memes  malades  de  la  paraplegie 

cerebrale  infantile  et  de  la  paralysie  spinale  infantile.  Nouv. 

Iconog.  de  la  Salpetriere,  Par.,  1907,  xx,  122-145. 
Russel,  C.  K.  Study  of  epidemic  encephalitis  based  on  seventeen 

cases  with  two  necropsies.  J.  Can.  M.  Assn.,  1920,  x,  696. 
Russell,  W.  B.  A  case  of  acute  encephalitis.  Lancet,   1918,  ii,  106. 
Sabatini,  G.  Lethargic  encephalitis;  symptoms  and  course.  Abstr., 

J.  Am.  M.  Assn.,  1920,  Ixxiv,  1057. 
Sachs,  B.  Polio-encephalitis  superior  (nuclear  ophthalmoplegia) 

and  poliomyelitis.  Am.  J.  M.  Sc.,  1889,  xcviii,  248-254. 
Epidemic  central  or  basilar  encephalitis.  N.  York  M.  J.,  19 19, 

cix,  894. 
Saethre,  H.  Lethargic  encephalitis,  a  new  disease?  Tidsskr.  f.  d. 

norske  Laegefor.,  Kristiania,  19 19,  xxxix,  705,  763. 
de   Saint   Martin   and   Lhermitte,    J.   La   poliomesocephalite 

primitive  avec  narcolepsie.  Progres  med.,  Par.,   1918,  xxxiii, 

213;  ibid.,   1918,  xxix,  64;  Bull,  et  mem  Soc.  med.  d.  hop.  de 

Paris,  19 1 8,  xlii,  457-462. 
Sainton,  P.  Encephalite  Iethargique  a  forme  subaigue.  Bull,  et 

mem.  Soc.  med.  d.  hop.  de  Par.,  191 8,  xlii,  543-549- 
Encephalite  Iethargique.   Bull,   et  mem.   Soc.   med.   d.   hop.   de 

Par.,  19 1 8,  xlii,  424-427. 
Sampietro,    G.    Epidemic   encephalitis.    Ann.    d'Igsper.,    Roma, 

1920,  xxx,  45. 
Schaeppi,   T.   Lethargic   encephalitis.    Schweiz.   med.    Wchnschr., 

1920,  1,  581. 
Schroeder,  P.  Encephalitis  and  myelitis.  Monatschr.  j.  Psychiat. 

u.  Neurol.,  BerL,  191 8,  xliv,  146-19 1. 
Schulze,  M.   Encephalitis  Iethargica  in  pregnancy.  J.  Am.M. 

Assn.,  1920,  Ixxiv,  732. 
Schwartz,  S.  Lethargic  encephalitis.   Report  of  cases.  N.   York 

M.  J.,  Aug.  7,  1920,  p.  182. 
Sharfin,  Z.  Encephalitis  in  an  infant  following  influenza.  N.  York 

M.  J.,  1920,  cix,  ^y6. 


256  ACUTE  EPIDEMIC  ENCEPHALITIS 

Shaw,  J.  F.,  and  Bartlett,  F.  H.  Report  of  a  case  of  encephalitis 

Iethargica.  J.  Am.  M.  Assn.,  1918-1919,  ix,  284-286. 
Sicard,  J.  A.   Myoclonic  encephalitis.  Presse  med.,   Par.,    1920, 

xxviii,  213;  abstr.,  J.  Am.  M.  Assn.,  1920,  Ixxiv,  1547. 
Sicard,  J.  A.,  and  Kudelski.  Myoclonic  acute  encephalitis.  Bull. 

et  mem.  Soc.  med.  d.  hop.  de  Paris,   1920,  p.  94;  abstr.,  J. 

Am.  M.  Assn.,  1920,  Ixxiv,  1055. 
Siemerling,    E.    Uber    eine    Enzephalitisepidemie.    Berl.    klin. 

Wchnschr.,  19 19,  Ivi,  505-509. 
Skoog,  A.  L.  Encephalitis  Iethargica.  J.  Kansas  M.   Soc,    1920, 

xx,  1-4. 
Skversky,  A.  Lethargic  encephalitis  in  the  A.  E.  F.:  A  clinical 

study.  Am.  J.  M.  Sc,  Phila.,  19 19,  clviii,  849-863. 
Smith,  J.  A.  Three  cases  of  epidemic  stupor.  Lancet,  191 8,  i,  737. 
Spaeth,  E.  B.  Ocular  symptoms  in  lethargic  encephalitis.  Military 

Surgeon,  Washington,  1920,  Ixvii,  230. 
Speidel.  Late  results  of  encephalitis  after  influenza.   Milnchen. 

med.  Wchnschr.,  1920,  Ixvii,  630. 
Spielmeyer,   W.   Ein   Beitrag  zur  Kenntniss   der   Encephalitis. 

Arch.  j.  Psychiat.,  Berl.,  1902,  xxxv,  676-691. 
Uber  die  Prognose  der  akuten  hemorrhagischen  Polioencephalitis 

superior  (Wernicke).  Centralbl.j.  Nervenh.  u.  Psychiat.,  Coblenz 

&  Leipz.,  1904,  xxvii,  673-691. 
Stafford,  C.  M.  Encephalitis  Iethargica.  J.  Lab.  &  Clin.  Med., 

191 8-19 19,  iv,  691-694. 
Stahelin,  R.  Epidemic  encephalomyelitis.  Schweiz.  med.  Wchnschr., 

1920,  1,  201;  abstr.,  J.  Am.  M.  Assn.,  1920,  Ixxiv,  1289. 
Stanton,  J.  M.  Epidemic  encephalitis.  A  critical  review.  Mod. 

Med.  1920,  ii,  353. 
Stauffenberg,  von.  Ein  Fall  von  Encephalitis  peri-axialis  diffusa 

(Schilder).  Monalschr.  f.  Psychiat.   u.   Neurol,   Berl.,    19 18, 

xliv,  56-70. 
Strauss,  I.,  and  Hirschfeld,  S.  Studies  in  epidemic  encephalitis 

(encephalitis  Iethargica).  N.  York  M.  J.,  19 19,  cix,  772. 
Strauss,  I.,  and  Loewe,  L.  Etiology  of  epidemic  encephalitis.  J. 

Am.  M.  Assn.,  1919,  Ixxiii,  1056. 
Studies  in  epidemic  (lethargic)  encephalitis.  J.  Inject.  Dis.,  1920, 

xxvii,  251. 
Strumpell,  A.  Epidemic  (lethargic)  encephalitis.  Deutsch.  med. 

Wchnschr.,  Berl.  &  Leipz.,  1920,  xlvi,  705. 


BIBLIOGRAPHY  257 

Uber   die  akute   Encephalitis  der  Kinder.  Jahrb.  j.  Kinderh., 
Leipz.,  1884,  xxii. 
Taylor,  E.  W.  Polioencephalomyelitis.  Boston  M.  &  S.  J.,  1903, 

p.  634. 
Tilney,    F.    Poliomyelitis   with   prolonged   somnolence.    Neurol. 

Bull,  19 1 8,  i,  7. 
Tilney,  F.,  and  Howe,  H.  S.  Epidemic  encephalitis  (encephalitis 

Iethargica).  New  York,  1920. 
Tilney,  F.,  and  Riley,  H.  A.  Epidemic  encephalitis  with  a  con- 
sideration of  some  of  its  prominent  clinical  and  pathological 

manifestations.  Neurol.  Bull,  1919,  ii,  106-135. 
Tobler,  T.  Lethargic  encephalitis.  Schweiz.  med.  Wchnschr.,  1920, 

Nos.  23  and  24,  p.  446. 
Tucker,    B.    R.    Epidemic   encephalitis    Iethargica   or    epidemic 

somnolence,  or  epidemic  cerebritis,  with  report  of  cases  and 

two  necropsies.  J.  Am.  M.  Assn.,  1919,  Ixxii,  1448-1450. 
Tucker,  B.  R.,  and  Budd,  S.  W.  Epidemic  encephalitis  Iethargica, 

with  especial  reference  to  etiology  and  pathology.   Virginia 

M.  Month.,  1919-1920,  xlvi,  228-232. 
Ulrich,  G.  R.  Case  of  lethargic  encephalitis,  abstr.  J.  Am.  M. 

Assn.,  1920,  Ixxiv,  640. 
Vaidya,  S.  K.  Obscure  epidemic  encephalitis.  Some  observations 

on  blood   counts   and   cerebrospinal   fluid.   Lancet,    19 18,   ii, 

322-323. 
Vaughan,  V.  C.  Encephalitis  Iethargica.  J.  Lab.  €f  Clin.  Med., 

1918-1919,  iv,  381-386. 
de    Verbizier.    Deux    observations    d'encephalite    Iethargique. 

Paris  med.,  19 18,  xxviii,  suppl.,  345. 
Vest,  W.^E.  Encephalitis  Iethargica.  West  Virginia  M.  J.,  19 18- 

19 19,  xiii,  454-459- 
Volpino,  G.,  and  Desderi,  P.  Microscopy  of  epidemic  encephalitis. 

Ann.  d'Igsper.,  Roma,  1920,  xxx,  81. 
Wechsler,  I.  Symptoms  of  epidemic  encephalitis  structurally  and 

functionally  considered.  N.  York  M.  J.,  Aug.  7,  1920,  p.  175. 
Wegefarth,   P.,    and  Ayer,   J.    B.    Encephalitis   Iethargica.    J. 

Am.  M.  Assn.,  19 19,  Ixxiii,  5-12. 
Weiland,    E.   Lethargic  encephalitis   in   children.   Schweiz.   med. 

Wchnschr.,  1920,  1,  581. 
Wernicke,    C.    Polioencephalitis  .hemorrhagica    superior   acuta, 

Lehrbuch  der  Gehirnkrankheiten  (Wernicke),  Kassel,   1881, 

p.  47. 


258  ACUTE  EPIDEMIC  ENCEPHALITIS 

Wickman,  I.  Cerebral,  pontile  and  bulbar  forms  of  the  Heine- 

Medin  disease.  Uber  die  akute  Poliomyelitis  und  verwandte 

Erkrankungen  (Heine-Medinsche  Krankheit).  Jahrb.  f.  Kind- 

erh.,  Leipz.,  1908,  Ixvii,  182-196. 
Poliomyelitis,  New  York,  19 15. 
Widal,    F.,    and   Achard,   L.    E.    Encephalopathie   Iethargique. 

Reaction  meningee.  Morcellement  du  syndrome  pyramidal. 

Bull.  Acad,   de  med.,   Par.,    1920,   Ixxxiii,   81-84;   abstr.,   J. 

Am.  M.  Assn.,  1920,  Ixxiv,  919. 
Widal,   F.,   et  al.   Encephalite  Iethargique.   Bull,   et   mem.   Soc. 

med.  d.  hop.  de  Par.,  1920,  xliv,  922,  929. 
Wiesner,  von.  Die  Aetiologie  der  Encephalitis  Iethargica.  Wien. 

klin.  Wchnschr.,  191 7,  xxx,  933-935. 
Wilbrand,  H.,  and  Saenger,  A.  Polioencephalitis  hemorrhagica; 

polioencephalomyelitis.    Neurologie   des   Auges,    Wiesbaden, 

1900,  Bd.  1. 
Wilson,  J.  A.  The  bacteriology  of  certain  filter-passing  organisms. 

Brit.  M.  J.,  19 1 9,  i,  602-604. 
Wilson,  S.  A.  K.  Epidemic  encephalitis.  Lancet,  1918,  ii,  7-12,  91. 
Winslow,  K.  Epidemic  lethargic  encephalitis  (Nona)  in  Seattle. 

Northwest  Med.,  1919,  xviii,  209. 
Woods,  H.  Cases  of  lethargic  encephalitis.  Arch.  Ophth.,    1919, 

xlviii,  536. 
Lethargic  encephalitis,  Am.  J.  Ophth.,  19 19,  ii,  866-870. 
Woolley,  P.  G.  Encephalitis  Iethargica.  J.  Lab.  €f  Clin.  Med., 

191 8-19 19,  iv,  456. 
Wylie,  A.  Peritonsillar  abscess  followed  by  osteomyelitis,  necros- 
ing encephalitis  and  meningitis.  Lancet,  19 19,  i,  178. 

ENCEPHALITIS  IN  HORSES 

Encephalitis  in  Horses,  Current  Comment.  J.  Am.  M.  Assn., 
1920,  Ixxiv,  1 172. 

Kraus,  R.,  Kantor,  L.,  and  Quiroga,  R.  Enzootic  meningo- 
encephalitis. Rev.  d.  Inst.  Bacteriol.,  Buenos  Aires,  19 19,  ii, 
239;  abstr.  J.  Am.  Med.  Assn.,  1920,  Ixxiv,  1198. 

Buckley  and  MacCallum,  W.  G.  Hemorrhagic  encephalitis  of 
horses.  Am.  Vet.  Rev.,  1900,  p.  99. 


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